Springer Semin Immunopathol (1984)7:387-413

Springer Seminars in Immunopathology © Springer-Verlag 1984

Cytokines and Other Mediators in Rheumatoid Arthritis Jean-Michel Dayer and Stephen Demczuk Divisionof Immunologyand Allergy(Hans WilsdorfLaboratory),Departmentof Medicine,University Hospital Cantonal, CH-1211 Geneva 4, Switzerland

Introduction In rheumatoid arthritis (RA) and other chronic inflammatory connective tissue diseases, inappropriate activation of the circulating or resident cells becomes selfperpetuating and can lead to chronic tissue destruction 1-81, 109, 218]. Such a selfdestructive mechanism may persist beyond the initial stimulus (which is still unknown in RA) and into later stages of frank tissue injury. The participants of the inflammatory response to tissue injury involve cells that in part serve directly in the immune response or act through various mediators which cannot be eliminated or inhibited. Such mediators at any stage of acute or chronic inflammation may be both deleterious or beneficial. The distinction between specific reactions associated with a particular inflammatory tissue disease from those of general inflammatory processes is most difficult. The non-immune events may involve numerous interactions with hormones and extracellular elements of the organic and inorganic matrix. This review will specifically focus on the roles of some cellular mediators involved in the different inflammatory phases of rheumatoid arthritis. The general concensus among investigators is to place the developing sequence of RA into the following phases [34, 81]. 1. Exudative and cell recruitment phase. 2. Differentiation and proliferative phase. 3. Destructive phase along with synovial cell, chrondrocyte, and osteoclast activation. 4. Fibrotic and repair phase.

1. Exudative and Cell Recruitment Phase The early lesion consists of mild proliferation of the synovial lining layer together with vascular engorgement and edema [112, 217]. Microvascular lesions may be Supported in part by a grant No 31449.0.83from the Swiss National ScienceFoundation Offprint requests to:

J.-M. Dayer

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prominent, leading to the obliteration of small blood vessels by organized thrombi. The vascular hypothesis, including endothelial cell injury as the pathogenesis of rheumatoid arthritis has been extensively reviewed elsewhere [164]. The predominant feature early in the development of RA is perivascular lymphocyte infiltration with fewer polymorphonuclear leukocytes (PMN) located in the superficial layer of the synovium. Most of the PMN are found, however, in the synovial cavity. There is no direct evidence that the etiologic factor of RA is carried to the joint from the circulation; neither do the initial "activated" cells come from the peripheral blood cells nor do they preexists in the normal synovial tissue [110]. Phagocytosis of immune complexes by PMN or synovial cells may be also important in the initial phase as well as in the latter destructive phase of RA [201]. Since the exact sequence of the initial events is not actually known, one can only list participants suspected in playing a principal role in the acute exudative phase (Table 1). Among them are (a) the vasoactive amines (histamine, bradykinin, serotonin); (b) the clotting and fibrinolytic components (Factor XI, plasminogen activator, fibrin fragments D and E); (c) the leukocyte products (icosanoids, interleukins); and (d) the fragments of complement (mainly C3b and C5a). The complex interplay among these mediators account for the rubor-calor-dolor (redness, heat, and pain) clinical aspect. Recent work has placed emphasis on the importance of members of the icosanoid family. Icosanoids (general term used for a family of lipid mediators of 20 carbons in length, also called prostanoids) are derivatives of the unsaturated fatty acid linoleic acid. Dihomo-7-1inoleic acid and arachidonic acid are esterified in the phospholipid moiety of cell membranes. The release of these mediators from the cell membrane enables them to become precursors to prostaglandin series "1" and "2", respectively [111, 187]. As the result of a high dietary intake of e linoleic acid found in fish, the formation of a third precursor is formed. This precursor (i. e., eicosapentaenoic acid) gives rise to the "3" series of prostaglandins [57]. This is of considerable interest since inflammation may be attenuated via eicosapentaenoic acid (EPA) acting to alter the production of thromboxanes, prostaglandins, and leukotrienes [202]. High dietary levels of EPA can then produce alterations in platelet function normally regulated by prostaglandins and thromboxanes [49]. A diet enriched in EPA has also been shown to delay the development of proteinuria and to prolong survival in (NZB x NZW)F 1 mice [152]. Finally this diet can also enhance the production of IgE and IgG antibodies in the rat [153]. The precursor to the major icosanoids (i. e., arachidonic acid) is cleaved from membrane lipids by phospholipases and is then metabolized by either t h e "lipoxygenase" or the classical "cyclo-oxygenase" pathway [111]. These two divergent pathways from arachidonic acid are expressed to various degrees by cells involved in the inflammatory response. For example, for the lipoxygenase-derived products, the platelets contain mainly 12-1ipoxygenase, neutrophils possess a considerable amount of 5-1ipoxygenase, and the lymphocytes mainly 15-1ipoxygenase [169]. The lipoxygenase-derived products, especially the LTB 4 produced by PMN are prodigious cellular chemoattractants [62]. Aberrant polymorphonuclear leukocyte chemotaxis has been reported in rheumatoid arthritis [ 129, 191]. Via the 5-1ipoxygenase pathway, the unstable intermediate LTA 4 is also derived from arachidonic acid. When conjugated to glutathione, this fatty acid metabolite (LTC4)

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Cytokines and Other Mediators in Rheumatoid Arthritis Table 1. Phase 1: Exudative and cell recruitment phase Local mediators

Principal cell origin

Major biologic effects

Reference

Histamine Bradykinin, kinins Serotonin

Basophils and mast cells Platelets

Vasodilation (arteriole) 10, 26, 146, 164 Increase permeability (venule)104, 132 Pain (pain ending C-fibers) 61, 215

IL-1 MO (EP, endogenous pyrogen) M~ (LEM, leukocytic mediator)

Fever, chemotaxis Increase acute phase reactive protein

47, 114, 141 103

Prostaglandin (PGE2)

MI~,platelets,

Vasodilatation, pain,

Prostacyclin ( P G I 2 )

endothelial cells

Leukotriene B4

PMN M0

vasodilatation, plateletaggregating inhibitor Increase permeability, chemotaxis, phagocytosis, PMN attachment, and aggregation

69, 111, 161, 187, 194 111, 187 62, 115, 148 29, 142 129

Leukotrienes Ca, D4

M0 PMN

Vasoconstriction (arteriole), 29,142 extravasation from post capillary venules

Platelet activating factor (PAF)

Basophils PMN attachment to PMN M~, platelets endothelium,platelets aggregation, vasoactive amine release, leukotrienes production

186, 197 145, 165

Phospholipase A2

M~), PMN

Production of biologically active lipids

94, 192, 193

C5a

M0, serum via hepatocytes

PAF production, M0 chemotaxis, lysosomal enzyme release

C3b

MO, serum via hepatocytes

Facilitatesphagocytosis, MO activation

201, 170

Fibrin-derived peptides (D and E fragments)

M~J, s e r u m

Permeability, chemotaxis for PMN and M0

64, 168

82, 200, 201

becomes L T D 4 and L T E 4 by successive loss of glutamate and glycine, respectively [169]. These products, which constitute the slow reactive substance of anaphylaxis (SRS-A), are synthesized in considerable quantities by macrophages, mast cells, and basophils which are also present in the synovial tissue [26]. In view of the large amounts of P M N in the synovial fluids, the role of leukotrienes in rheumatoid arthritis is likely to be important in vascular permeability and chemotaxis [69]. Recently, it has been found that the synovial fluid P M N do not release measurable a m o u n t s of 5-1ipoxygenase products, but do so after stimulation by the calcium i o n o p h o r e A23187. The major icosanoid products from i o n o p h o r e stimulation are 5 - H E T E and LTB4, but not LTC4, although the p r o d u c t i o n of this leukotriene in the peripheral P M N is considerable. This lack of L T C 4 production by

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synovial fluid PMN may indicate that an alteration has occurred in their arachidonic acid metabolism. In contrast, the mononuclear cells of the synovial fluid release 5-HETE, LTB4, and LTC 4 [148]. A number of pathogenomic features of RA have been attributed to the metabolites of cyclooxygenase. The correlation between RA and the cyclooxygenase-derived products has been studied extensively [127, 161]. In the early phase of RA, these icosanoids have been shown to be responsible for vasodilatation and the increased sensitivity to pain [194]. This is followed by prostaglandin modulation of the immune response and particularly macrophage Ia expression in mice [177]. In the destructive phase of RA (to be discussed), prostaglandins are also involved in osteoclast activation and bone resorption [ 130, 155]. In addition, prostaglandins have been shown to control the fibrotic phase by modulating collagen synthesis [39, 143, 181]. Many experiments have been done in animal models. Arthritis in the rat generated through adjuvant injections in the joint, is ameliorated through the administration of pharmacological doses of PGE 1 [216]. In NZB x NZW mice, immune complex-induced glomerulonephritis and their suvival is also improved by the injection of pharmacological doses of PGE 2 [106, 113, 122]. The complex and sometimes contradictory role of PGE2 in immune response in vitro has been extensively reviewed by Goodwin and Ceuppens [73]. PGE 2 is thought to act as a feedback inhibitor of many cellular immune responses, including mitogen-induced proliferation of T cells and B cells, T cell cytotoxicity, lymphokine production, natural killer activity and macrophage cytotoxicity. Non-steroidal anti-inflammatory drugs, in vitro, cause increased activity in all of these assays. In regard to the in vitro humoral immune response these authors suggest that the major function of PGE z is a selective inhibition of T suppressor cell function. As a consequence of this inhibition, PGE 2 can then induce or increase auto-antibody production [162]. Non-steroidal anti-inflammatory drugs release suppressor T cells from their inhibition, resulting in a decreased total immunoglobulin production. Other groups have also demonstrated that endogenous PGE 2 production is important in providing a "drive" for stimulated mononuclear cells to produce immunoglobulins in vitro and that indomethacin strongly inhibits this response from cells of normal healthy individuals. However, this inhibition was poor on cells of rheumatoid arthritis patients [178]. In contrast, recent in vivo data have shown that inhibitors of cyclooxygenase reduce serum RF levels in patients with rheumatoid arthritis [74]. Other studies from Hasler et al. [84] have shown that blocking PGE z production may partially correct a basic immunologic dysfunction in the RA patients. They have shown that T lymphocytes from patients with RA have an impaired ability to suppress B-lymphocyte activation by Epstein-Barr virus. This inability to generate suppressor cells can be corrected by the addition of indomethacin to the mononuclear cell cultures. As mentioned previously the role of PGE 2 in the immune response is still confusing [73]. It appears that in addition to being suppressive of T-cell functions, PGE z is required in the generation and action of other types of suppressor cells. Recently, for example, the mechanism of controlling human IL-2 production has been clarified by demonstrating that PGE 2 activates radiosensitive suppressor T lymphocytes [22]. Further advances and clarification in this field may be possible

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when other cyclooxygenase metabolites as well as lipoxygenase products have been studied. One must be also critical in relating these in vitro results to the in vivo situation since the pathophysiologic response to PGE 2 may vary due to the target cell or to the particular function analysed. The question still remains open as to the overall importance that icosanoids have in rheumatoid arthritis. Blood monocyte-macrophages from RA patients produce significantly more PGE 2 than do these cells from healthy donors [27, 174]. This relative increase was more striking when these cells were first stimulated with concanavalin A [27]. It may well be possible that (depending on the phase of inflammation) a given icosanoid will be detrimental or beneficial to the progression of the disease. For example, in the early phase, PGE 2 is "pro-inflammatory" by inducing vasodilatation and pain. Later, PGE 2 may be considered as "antiinflammatory" by inhibiting the T-suppressor function and the production of certain lymphokines [68]. Another important factor, the platetet-activating factor (PAF) is also a membrane lipid derivative. PAF is a n alkyl-ether analogue of phosphatidylcholine containing an acetyl group at position 2 of the glycerol chain [186]. This factor is synthesized by a variety of cells present in the rheumatoid lesion and acts on other cells such as neutrophils and platelets. It functions mainly in platelet aggregation and release of vasoactive amines [145, 165, 197]. Platelets by themselves have also been a source of PAF. Extracellular phospholipase A 2 (PLA2) has recently been described in the rheumatoid arthritis patient [192]. Two distinct pools of PLA 2 exist within mammalian cells, the ubiquitous membrane associated and the soluble lysosomal PLA 2 [94]. In response to various stimuli, lysosomal PLA2 is released extraeellularly, where it cleaves the phospholipid constituent of the plasma membrane of neighboring cells. This generates biologically active lipids which are vasoactive, inducers of vascular permeability, cytotoxic, and chemotactic for PMN and macrophages [-193]. Extracellular PLA 2 has been found to be elevated in all synovial fluids of patients with RA [192]. In the early acute inflammatory phase of rheumatoid arthritis, it is likely that the monokine interleukin 1 acts analogously to endogenous pyrogen (EP)) in inducing fever, leukocytic endogenous mediator (LEM) [103, 141], and/or hepatocytestimulating factor (HSF) in stimulating acute phase reactant protein synthesis [158] and again to LEM by lowering plasma Fe + + and Zn + + levels. These subjects have been extensively reviewed elsewhere [47]. In addition, increased vascular permeability and PMN/macrophage chemotaxis may be due to the vasoactive peptides derived from the degradation of the acute phase reactant fibrinogen and its product. fibrin [64, 168]. 2. Differentiation and Proliferative Phase

The histopathology of chronic rheumatoid arthritis has been well described [81, 112, 217]. However, what is not well established is the cellular origin of the proliferating synovitis in rheumatoid arthritis. Evidence is lacking as to whether the origin of these cells is from the synovium itself (resident cells) or from the blood stream (non-resident cells). The prinicipal cells contained in the pannus are listed in

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Table 2. Cellular elements in rheumatoid synovium and adjacent structures Histologic localization

Cell types

Major products or functions

Superficial lining layer

Synovial "A" cells (macrophage-like) Synovial "B" cells (fibroblast-like) "Stellate-dendritic" cells

Phagocytosis Proteases, PGE 2 Collagens, hyaluronic acid

Interstitial layer

Fibroblast Monocyte-macrophages T lymphocytes B lymphocytes Mastocytes

Collagens, fibronectin IL-1 (MCF), IFN-a, PGE z MIF, IFN-7, IL-2 Rheumatoid factors Histamine, IL-3

Blood vessel

Endothelial cells smooth muscle cells Platelets

PGI2, PGE 2 PGE z Thromboxanes, PGE a

Synovial fluid

Mainly PMN

Leukotrienes

Adjacent structures

Chondrocytes Osteoblasts Osteoclasts

Proteoglycan, chondronectin, Collagen, osteonectin Mineral phase resorption

Collagenase, PGE 2 Plasminogen activators

Table 2. Histologic examination at the early stage of RA indicates numerous small vessels. This has been attributed to a large increase in numbers of vascular cells [164, 176]. The blood vessels in the synovia of patients with a number of different arthropathies are identical to the high endothelial venules (HEV) of the lymph node paracortex, known to be the site of lymphocyte diapedesis [96]. These endothelial venules in the synovium appear to be the primary site for vasodilatation leading to lymphocyte diapedesis and protein exudation [63,164]. Shortly after vascular changes, the cells of the synovium proliferate, leading to a more heterogeneous pannus cell population. The ultrastructural examination of the synovial lining has identified several cell types: (1) type "A" (macrophage-like); (2) type "B" (fibroblast-like) with cell processes, prominent rough endoplasmic reticulum, and vacuoles; and (3) type "C" (intermediate cell) which possess endoplasmic reticulum, vacuoles as well as Golgi complexes. This classification is probably arbitrary since a change in stimulus could alter their physiological function, since it is known to alter their cytoskeleton architecture [7]. Cytohistochemical studies have provided a description of other cell types in the synovium [79]. These resemble the"stellate-dendritic" cells observed in cell cultures obtained from proteolytically dispersed synovia. In vitro studies suggest that these cells are the major source of collagenase and prostaglandin E 2 [35]. Better identification of synovial tissue cells can now be accomplished using monoclonal antibodies. Different types of synovial lining cell populations have been identified by monoclonal antibodies directed to Ia ÷ antigens and antigens associated with monocytes/macrophages and fibroblasts [17]. Lymphocyte infiltration is also observed in the superficial layer of the synovial membrane with plasma cells and macrophages entering in the perivascular region.

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Small lymphocytes which emigrate perivascularly are among the first cell types to accumulate in the superficial layer of synovium. Nearby, there are transitional areas where small lymphocytes undergo blastic transformation. For example, stimulated T lymphocytes become T lymphoblasts and B lymphocytes become plasmablasts. Macrophages are also present, as are a small number of fibroblasts [150, 34, 81,108, 175]. Controversy exists over the proportion of the T cells that display OKT4 + helper cell and OKT8 + suppressor/cytotoxic cell markers. Compared to their distribution in the blood a slight increase in OKT8 + cells has been observed when T cells are released from enzyme-digested synovial tissue [16, 48]. The transitional •areas exhibit a predominance of OKT4 + helper cells. The role of the interactions between subpopulations of T cells and B cells in the pathogenesi s of RA has been reviewed elsewhere [53, 67, 99]. The interaction through physical contact and/or soluble mediators between the various cell types within the synovium has for many years led to the speculation that abnormal cytokine production occurs in the rheumatoid joint. Stastny et al. [179] have observed macrophage inhibitor factor (MIF) activity (Mr 23 000 daltons) in the synovial fluids of 18 out of 22 RA patients, 4 out of 11 patients with various inflammatory arthritises, and 3 out 15 patients with osteoarthrosis. MIF activity has also been found in 9 out of 11 supernatants of 48hour cultured synovial tissues from RA patients. MIF-like activity has also been detected in the pericardial fluid of a patient with rheumatoid pericarditis [6]. An abnormal production of another lymphokine, the leukocyte migration inhibition factor (LIF), has been found in blood mononuclear cell cultures from patients with RA and in supernatants of cultured mononuclear cells isolated from rheumatoid synovial tissue [21]. The elevated expression of LIF is not specific to RA since high levels are also found in Reiter syndrome and ankylosing spondylitis [52]. Studies have also been performed to determine whether blood mononuclear cells of RA patients exposed to normal synovial and cartilage tissues develop cellular immunity as determined by the LIF assay. These studies show that the lymphocytes from more than 50~o of the patients with RA produce a significant LIF activity when exposed to extracts from normal synovial membrane and articular cartilage. No correlation could be found between the extent of inhibition of LIFinduced migration and the severity of the disease. Trentham et al. have reported that RA patients exhibit significant cellular immune responses to Type II and III collagens, as measured by the levels of LIF in the medium produced by cultured peripheral blood mononuclear cells [189]. Stuart et al. have also observed that an increase in lymphocyte-derived chemotactic factor for monocytes results from cultured peripheral blood mononuclear cells from normal subjects exposed to collagen [ 182]. Other studies have shown that LIF released from mononuclear cells exposed to Type I1 and III collagen is restricted to cells from rheumatoid subjects, however the collagen-induced mononuclear cell factor (MCF) and PGE 2 is released from cells isolated from the normal and rheumatoid patient [42]. Human interferon (IFN) has been detected in the serum of patients with a variety of rheumatic diseases. These include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, and Sj6gren's syndrome [93]. Recently, the circulating IFN in these patients was identified as the IFN-e [151] in contrast to what had originally been assumed, i.e., IFN-7. IFN (IFN- 7 type probably) was

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frequently found either in the synovial fluid or the serum but generally not in both sites. The highest titers of IFN were found in the synovial fluid of patients with RA as compared to other rheumatic diseases [20]. However, in vitro studies have shown that normal T cells produce IFN- 7 when activated in an autologous mixed leukocyte reaction (auto-MLR) while those from RA patients do not. Both cell types express IFN-? in response to an allogenic activation [84]. In analyzing the contribution of the autologous non-T stimulator cells to that RA defect, it has been found that depletion of adherent monocytes from the auto-MLR stimulator population resulted in increased IFN- 7 and normal control of EBV-induced B cell proliferation in the RA auto-MLR supernatants [84]. The same authors found that the defective control of EBV-induced B cell proliferation by auto-MLR supernatants from RA patients had apparently resulted from a diminished capacity of their T cells to generate IFN-? when exposed to monocyte-derived prostaglandins. It is of interest to note that in these experiments, indomethacin corrects the RA defect [85]. Sera of seropositive RA patients are known to contain lymphocytotoxic antibodies [87]. The role of these antibodies in the pathogenesis of RA is unknown, although in vitro they have an increased reactivity to Ia antigens present on lymphoblasts. This suggests that lymphocytotoxinsmay play an immunoregulatory role in this disease [207]. A significant increase in occurrence of lymphocytotoxins was observed in the sera of patients with RA who possess the HLA-DR4 antigen as compared with those of other HLA-DR types. Furthermore, it was reported that the intensity of lymphocytotoxicity,i. e., the percentage of target lymphocytes lysed by a given serum, was greater in patients with HLA-DR3 [173]. A recent familial study showed that there was an increase in lymphocytotoxic activity in the sera of consanguineous relatives of patients with RA, and a strikingly high prevalence of lymphocytotoxins in the sera of unaffected spouses compared with a very low prevalence in random normal subjects [87]. The cytokine, interleukin 1 (to be discussed), has been found in the synovial fluid of patients with rheumatoid arthritis and other inflammatory arthropathies [60, 206]. Similarly, interleukin 2-like activity has been demonstrated in the synovial fluids of rheumatoid arthritis patients [204]. In contrast, cultured mononuclear ceils from systemic lupus erythematosus patients show a decreased production of interleukin 1 and interleukin 2 [116]. Impaired IL-2 production was not restored in vitro by IL-1 addition. This defect is known not to correlate with disease activity [78]. In animal models, investigators have reported that development of an SLElike syndrome in certain mouse strains correlates with a marked defect in IL-2 activity [1]. As shown in Table 3, the pathogenesis of RA involves a number of agents which play important roles in cellular differentiation and proliferation. One such protein is lipomodulin, also known as macrocortin [58, 91]. The induction of suppressor T cells, but not helper T ceils, and the differentiation of the monocytic cell line U937 has been attributed to lipomodulin [86]. Antibodies to lipomodulin can inhibit these responses. Autoantibodies against lipomodulin have been also found in patients with rheumatic diseases [92]. It can be speculated that the inactivation of lipomodulin through autoantibody production may contribute to the development of RA [90].

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Table 3. Phase 2: Differentiation and proliferative phase Local mediators

Principal cell origin

Major biologic effects

Reference

GM - CSF M-CSF ("IL-0")

T lymphocytes

IL-1 production, PGE 2 M0 differentiation

2, 37, 126, 128, 135

IL-1 (LAF)

M0

T lymphocyte activation

114, 124, 125

IL-2 (TCGF)

T lymphocytes

T lymphocyte proliferation

204

IL-3

Basophils, mast c e l l s

Differentiation and growth factor activities

95

Proteases

PMN, M0

Proteolysis, lymphocyte activation and proliferation

23

Angiogenic factor

Me

Endothelial cell proliferation

15, 59

Macrophage inhibitory factor (MIF)

T lymphocytes

Inhibits movement and cell spreading

6, 23, 179

Lymphocyte inhibitory factor (LIF)

Lymphocytes

Inhibits lymphocyte migration

21

Interferons

Lymphocytes Monocyte-macrophages Fibroblasts

Increases expression class I and II antigens and Fc receptors. Enhancement IL-1 production

183

PGE 2

M0

Increases functional T cell suppressors

Macrocortin Lipomodulin

M0, lymphocyte

Fibronectin, collagens, and their fragments

M0, fibroblast, mast cells, fibroblasts

2, 128 22, 187

Inhibition phospholipase 58, 86, 91 Histamine release Cellular differentiation 90, 92 Induction of T suppressor cell M0 activation, chemotaxis IL-1 production, PGE 2 and collagenase production

12, 42, 147 171, 195

3. Destructive Phase

Bone Resorption The initial stage of bone resorption is t h o u g h t to be the dissolution of the calcium-phosphate mineral phase, followed then by proteoglycan removal and collagen degradation. The mechanism by which the mineral phase of bone is removed is not fully understood. Possibilities include chelators, localized decrease in pH, or reduction of local ion concentration t h r o u g h the activation of an ion p u m p which favors the dissolution of the solid phase [81, 109, 110]. Prostaglandins (mainly PGE2) m a y also play a vital role since they increase bone resorption in vitro by stimulating osteoclastic activity, see Table 4 [213]. The lymphokine, osteoclast activating factor (OAF), has been shown to trigger osteoclast bone resorption. P G E 2 a p p e a r s also to be required for O A F production. M o r e recently, the regulation of bone resorption has been associated with 1L-l-like molecules [75]. It is also conceivable that i m m u n e mediators such as I F N - 7 p r o d u c e d by in-

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Table 4. Phase 3: Destructivephase along with synovialcell chondrocyte,osteoclast activation Local mediators

Principal cell origin

Major biologic effects

Reference

Osteoclast activating factor (OAF)

Lymphocytes

Mineral phase release

130, 155, 213

PGEz IL-1, (MCF, mononuclear cell factor)

M0, platelets M0

Osteoclast activation Collagenase and PGE2 production by synovial cells and chondrocytes

100, 161,213 34, 109, 110, 123 75

PMN extracts

PMN

Collagenase production

83

Catabolin Lymphotoxin

M0? Lymphocytes

Cartilage resorption Lymphocyteand endothelial cell killing

8, 167 87, 173,207

Cellular injury (lipid peroxidation) Bone Resorption

121

Synovial c e l l s PMN, M0 PMN, fibroblasts MO, synovialc e l l s fibroblasts

Collagenolysis Collagenolysis Proteoglycan lysis Collagenase activation

40, 208 119, 208 8, 55, 100 80, 123, 132

Fibroblasts

Synovial cell: collagenase production M0:IL-1 (MCF) production

12, 42

Oxygen PMN, M0 free radicals Epidermal growth factor Fibroblasts (EGF) Proteases Collagenase Elastase Cathepsin G Plasminogen activator plasmin Collagens and their fragments

flammatory mononuclear cells increase the sensitivity of bone cells to hormone action, such as parathyroid hormone, PGE2, and vitamin D3 (1,25(OH)2 D3). Resorption by direct cell contact with monocyte-macrophages has also been demonstrated in vitro [185]. Finally, it is noteworthy that endotoxin, bacterial lipopolysaccharides, and components of the complement are agents which can induce bone resorption 1-110, 130, 185].

Proteoglycan Degradation Proteoglycans (complexes of proteins and glycosaminoglycans) in cartilage and bone are depleted during the progression of synovitis. The principal glycosaminoglycans in cartilage and bone are hyaluronic acid, chondroitin-4-sulfate, and keratan sulfate. The degradation of proteoglycan involves the breakdown of the glycosaminoglycan, desulfation of the sugars, and proteolysis. The proteoglycans are degraded primarily by neutral proteases (e. g., P M N leukocyte elastase, cathepsin G) which hydrolyse peptide bonds in the core of the proteoglycan subunits. Once the aggregates of proteoglycans are broken up, fragments can be degraded intracellularly by lysosomal enzymes (cathepsin B and D, N-acetyl glucosamidase, /%galactosidase, arylsulfatase A) and hyaluronidase. Superoxide

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and hydroxyl free radicals are also responsible for the depolymerization of the proteoglycans [121]. Chondrocytes can be stimulated to secrete neutral proteinases by a number of agents (including monokines) produced in the pannus, some of which are similar to the mononuclear cell factor (MCF) which stimulates collagenase and PGE 2 synthesis from synovial cells 1-55, 100]. Experiments employing animal models have suggested that the exposure to bacterial cell wall peptidoglycan dimers induces an arthritogenic response. This may explain some of the pathogenesis of RA since bacterial cell walls may have similar antigenic determinants as do peptidoglycans of cartilage [31]. One can hypothesize that degradation products of proteoglycans are responsible for a positive feedback loop in chronic inflammation, by triggering a cascade of cellular events that lead to tissue destruction [2183.

Collagen Degradation The depletion of collagen fibers results from the combined action of collagenases and elastase originating from the cells of the pannus and synovial fluid PMN [109]. The chondrocytes and bone derived cells also contribute, although at a lesser degree, to the production ofproteases. Collagenase is a metalloprotease (Mr 30 00040 000 daltons) active at neutral pH. It cleaves the interstitial collagen molecules (Type I, II, and III) across helices, 3/4 of the distance from the amino-terminus between glycine and isoleucine in the ~1 (I) chains and between glycine and leucine in the ~2 chains [136]. Collagenase, except in the polymorphonuclear leukocytes, does not appear to be stored, but synthesized de novo and secreted as either a latent zymogen and/or an active single polypeptide [208]. The stimulation of collagenase synthesis in synovial fibroblasts is associated with increased levels of its cognant mRNA [131]. The inactive zymogen must be first activated by other proteases (trypsin like enzymes). Plasmin for example is an effective activator of latent rheumatoid synovial collagenase. Plasmin is generated from plasminogen activator produced by rheumatoid synovial cells [208]. PMN leukocyte serine proteinase(s) (elastase) has the capacity to cleave the nonhelical telopeptide regions of collagen which contain the intermolecular cross-links. Elastase has also been shown to degrade type III collagen in its helical region. In contrast, animal collagenases cannot attack type IV and V collagens, whereas the PMN elastase can [208]. The regulation of collagenase activity by activators and inhibitors produced by the same cells or neighboring cells is likely to contribute to the pathogenesis of RA. In addition to the synthesis of collagenase and the activation of its zymogenic form, the extracellular levels of several protease inhibitors also regulate collagenolysis. In the serum, the major macromolecular inhibitors of collagenase are ~2-macroglobulin and/~l-anti-collagenase. A number of other tissue inhibitors have recently been described to be produced by human tendon and dermal fibroblast cultures [208]. We will now specifically focus on the control of human synovial cell collagenase production by activated mononuclear cell mediators.

Control of Collagenase Production Collagenase production is regulated by interactions among cells in the pannus and cells from the blood stream. To understand these interactions and to assess the role

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of each cell type, the superficial layer and the villi of the synovium are dissected and dispersed with proteolytic enzymes. In culture, two major cell populations can be distinguished. One population, not adhering to the culture dishes, is composed predominantly of lymphocytes. The other population is adherent and heterogenous, consisting mainly of fibroblast-like (large cells) and macrophage-like cells (smaller cells) [35-]. The large adherent stellate cells possess several dendritic processes and large nuclei. They do not possess conventional macrophage markers such as receptors for immunoglobulins and complement fragments, nor do they produce any lysozyme activity. Two major products of these large fibroblast-like cells are collagenase and prostaglandin (PGE2). Fluorescent-labeled antibodies to synovial collagenase have suggested that they are the source of collagenase activity in RA. The morphologic stellate appearance of these cells may be due to the effects of the high ambient concentrations of PGE 2 working through cAMP [7]. The other population of smaller adherent cells have "macrophage-like" characteristics. These cells typically disappear by the second week of culture, yet the production of collagenase and PGE z persists. With continued cell culture and passage, however, the levels of both collagenase and PGE 2 decrease, although the kinetics of both differ. We reasoned that the "macrophage-like" cell might function as a mediator cell and not as an effector cell in collagen destruction. In fact, the monocytemacrophages release a soluble factor (monokine), mononuelear cell factor (MCF) which stimulates the stellate-dendritic cells to copiously produce more collagenase and prostaglandin [37]. From our experience, the human blood monocytemacrophages are not capable of secreting detectable collagenase. Although PGE 2 is present, its levels are substantially lower than in adherent stellate dendritic cells. Other investigators and ourselves have subsequently found that media from cultured fragments of synovium (containing all cells including monocytemacrophages) can also stimulate PGE 2 production by synovial cell culture [160]. Furthermore, the same culture media can stimulate chondrocytes, bone-derived cells, and to a lesser extent certain skin fibroblasts. Recently, we have demonstrated that not only can blood peripheral monocyte-macrophages produce MCF, but at the local level so do the monocyte-macrophages isolated from synovial fluid of rheumatoid patients [149]. In summary, these observations indicate that the monocyte-macrophages produce a mononuclear cell factor (MCF) which is important in modulating collagenase and PGE z production in other target cells, i.e., synovial cells. MCF belongs to the family of the IL-1. Highly purified preparations of IL-1, determined by the assay for lymphocyte activating factor (LAF) have a stimulatory effect on collagenase and PGE 2 production by synovial cells [125]. Similarly, purified preparations of human MCF have IL-1 activity. Recently two independent reports have shown that IL-1 can be detected in the synovial fluid of patients with rheumatoid arthritis or other inflammatory diseases [60, 206]. It is not known if all the biologic effects attributed to IL-1 are due to the same molecule that has been modified by post-translational events or due to individual proteins encoded by messenger RNAs transcribed from a family of related genes. Such genes could have diverged from a common ancestrial "IL-l-like" gene. Alternatively, these various biologic activities could have resulted from a target specific response triggered by a

Cytokinesand Other Mediatorsin RheumatoidArthritis

399

unique IL-1 molecule. Employing the assay for MCF (based on collagenase and PGEz-stimulating activity), we have been able to show "IL-1 like" mRNA activity following translation of poly (A +) RNA in frog oocytes [43]. Characteristics and Roles of a Monokine (MCF) which Stimulates Collagenase and PGE2 Production In view of the marked effect of this soluble monocyte-macrophage product on collagenase and PGE 2 production, further characteristics of MCF are relevant in understanding the mechanisms of inflammation and tissue destruction in rheumatoid arthritis. A plethora of interactions between cellular and humoral factors and elements of the matrix regulate the production of MCF (Fig. 1 A and B) [110]. Cellular Interaction. Cultured monocyte-macrophages release a basal level of MCF into the media. Upon the addition of lymphocytes, particularly lectin or antigenstimulated T lymphocytes, the production of this monokine is significantly enhanced. The level of this response is dependent on the ratio of monocytes to lymphocytes (unpublished results). A high lymphocyte to monocyte ratio will partially inhibit the production of MCF. Cell-cell contact is not required for this stimulation since supernatants from purified T lymphocytes or from cloned T lymphocytes contain a soluble factor(s) capable of stimulating monocytemacrophage MCF [2]. Elegant studies on cell-cell interaction and hormonal modulation have been carried out on the monocytic cell line U937. This monocyte-macrophage model expresses receptors for 1,25 (OH)2 D 3 [3], insulin [159], and Fc receptor [5, 128]. When grown as a suspension culture no basal level of MCF activity is released. However, when U937 cells are cocultured with several different human cloned T lymphocyte lines or mature peripheral blood T lymphocytes in the presence of lectin, MCF activity is released [-2]. The cell-free media from several cloned, lectinstimulated T lymphocyte lines (OKT4 + and OKT8 +/5 +) contain a factor which induces MCF production by the U937 cells [2]. Freshly isolated human blood lymphocytes can be enriched in OKT4 + and OKT8 + subpopulations by employing columns of Degalan beads and the "panning" technique [209]. The media from separately cultured OKT4 + and OKT8 + lymphocytes were shown to stimulate the freshly isolated and adherent blood-monocyte-macrophages to produce MCF [33]. Although such a technique provides only enriched T lymphocyte subpopulations, the above results go along with the finding ofAmento et al. using T cell clones [21. In several assay systems, T lymphokines have been reported to influence the function of monocytes. Some of these lymphokines belong to the family of the colonystimulating factors affecting the macrophage (CSF-M) [135]. Recombinant IFN- 7 does not stimulate MCF production in U937 cells [2]. Furthermore, this lymphokine(s) stimulates MCF production in U937 cells, inhibits their replication, induces their spreading, adherence, and their cell surface expression of OKM 1 antigen and Fc receptors [128]. Amento et al. [3] have found that 1,25 (OH)2 I) 3 could enhance the maturation of the cells and affect MCF production. No MCF activity is produced from U937 cells incubated with 1,25 (OH)2 D3 alone. However, the cells do release MCF when cultured in the presence of conditioned media from

400

Jean-Michael Dayer and Stephen Demczuk

A

B Lymphocytes ]

Antigens, lectins bacterial products ~

viruses,

Rheumatoid factors

I T Lymphocytes ~ - ~ . ~ ' \ PGE2 "ILo" \ \ (-~ ,~c. . . . . . ~9" \ " ,~or-tu)~v,t.~ XX

" IFN-~/ | Li~rOmmoOdesUlin ~ ~

(VltDs)j

I/Immune complexes / ~ Polysaccharides (LPS) / [,. Collagens

//

-....XN,

[ ~omonocytes]

"~

~ Monocyte-maorophagos~

"LAF" (T Lymphocytes - - P - IL-2 production)

DR+expression

"EP" (hypothalamus ~ fever) IL-1 ~

"LEM/HSF" (Hepatocytes Acute phase protein synthesis)

"EP" (muscle proteolysis)

"MCF" "MCF"'

/Ch°;dr°cytesl

Procollagenase l Elastase cathepsins

+ ~

~

-ISynOvialceusl (-)//Iv l . . . . . . .(-) ..

Increase hormonal response to PTH, PGE2

PGE2. . . .

~"

[

Collagen and --_ fibronectin synthesis \ A \

| Fibroblast proliferation

/[ Lymphocytes["~

"Active" collagenase

Lysis of proteoglycans

(CTAP) - - (i DGF)

Osteoclast~OAF activation

~

Fibroblast recruitment

Collagenolysis

v Bone resorption and tissue destruction

I f

v Attempt at repair and fibrosis

I

Fig. 1. Human cell culture model for the pathogenesis of connective tissue destruction in rheumatoid arthritis in relation with interleukin 1

Cytokinesand Other Mediatorsin RheumatoidArthritis

401

lectin-stimulated T lymphocytes. The U937 cells and the monocyte-macrophages also release significant amounts of plasminogen activator, while also secreting an inhibitor for plasminogen activator [ 196]. This enzyme and its inhibitor may play a crucial role in tissue destruction by controlling (via plasmin) the conversion of the latent collagenase to its active form at the local site of the inflammatory lesion [208]. Another cellular interaction has been recently suggested between PMN and synovial cells. Cytosol fractions of PMN cells (Mr 20 000 and 45 000 daltons) was shown to stimulate collagenase production by synovial cells [83]. Humoral Interaction. Since monocyte-macrophages have receptors for the Fc portion of immunoglobulins, immune complexes may also take part in MCF (IL- 1) production. The exposure of monocytes to heat-aggregated IgG or to fragments of the IgG, but not the monomeric IgG or Fab fragments, results in a marked increase in PGE 2 and MCF monocyte secretion [413. Recently, we have found that rheumatoid factors isolated from synovial fluid of rheumatoid arthritis patients can markedly stimulate PGE 2 and MCF production by monocyte-macrophages [133]. Lipopolysaccharide endotoxins act similarly, but this effect can be blocked by addition of polymyxin B [41]. Matrix Interaction. Cell behavior may be affected by interactions with macromolecules of the extracellular matrix. For example, their degradation products and fibronectin affect the replication and the chemotaxis of fibroblasts and monocytes [147]. Patients with rheumatoid arthritis and psoriatic arthritis exhibit a cellular immunologic response to native type II and III collagens, as measured by production of the lymphokine leukocyte inhibitory factor (LIF). Collagen also influences the production of MCF and PGE 2 by monocytes. Types II and III human collagen are most effective in stimulating MCF and PGE 2 production in normal and rheumatoid monocytes. This effect does not only occur through the native collagen fibrils, but to a lesser extent, from denatured collagen as well [42]. The inorganic phase of the bone (i. e., hydroxylapatite and calcium pyrophosphate dehydrate crystals) may also contribute to tissue destruction by stimulating MCF, collagenase, and PGE 2 production [214]. This observation may be relevant to the pathogenesis of other arthritic diseases such crystal-induced arthropathies. Other Biologic Actions of M C F on Synovial Cells

Partially purified MCF does not only stimulate collagenase and PGE 2 production in cultured synovial cells, but this cytokine is also known to affect other cellular functions, some of which depend directly on endogenous PGE 2 levels produced by synovial cells exposed to MCF. In the synovial cell culture system, endogenous and exogenously added PGE 2 inhibit cell replication. When PGE 2 production is blocked by indomethacin, MCF has a mitogenic effect on synovial culture cells. Changes in cellular morphology appear also to be related to levels of PGE 2 in culture. It is possible that the stellate aspect reflects the high level ofPGE 2 to which the cells are exposed. In this in vitro system, PGE2 alone does not stimulate collagenase production by the synovial cells, but may modify its response to MCF. Depending on the donor source, synovial cell cultures that have been stimulated by MCF in the presence of high pharmacologic concentrations (10 pM) of in-

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Jean-Michael Dayer and Stephen Demczuk

Table 5. Drug effects on MCF, PGEz, and collagenase production Monocyte-macrophages

MCF-stimulated synovial cells

PGE 2

MCF

PGE 2

Collagenase

Glucocorticosteroids

.~

$

+

~.

Nonsteroidal antiinflammatory drugs

$

~

1

Retinoids

~

T

~

$

Trifluoperazine

?

?

.L

T

Ic~,25 (OH)2 vit D 3

T

~

?

.9

domethacin decrease collagenase production. Collagenase production is restored in these cells by addition of low concentrations of PGE 2. The exogenously added PGE 2 or dibutyryl cAMP can overcome the indomethacin inhibition, indicating that PGE 2 modulates collagenase expression through cAMP [38]. On the other hand, even at low concentrations (0.1 pM) of indomethacin which still markedly inhibit PGE z synthesis, no change is observed in collagenase levels. Low concentrations (10 nM) of glucocorticosteroid block the production of both collagenase and PGE 2. These results suggest that nonsteroidal anti-inflammatory drugs are poor inhibitors of collagenase production and alone may not be sufficient to arrest collagen degradation in the RA patient. The effects of other drugs on MCF, PGE2, and collagenase production are summarized in Table 5 [14, 32, 36, 44]. Another aspect of MCF is in its induction of increased synovial cell sensitivity to PGE2, as determined by a PGE2-induced cAMP response. This cAMP response to PGE 2 exposure is not evident with MCF alone and only partially so with indomethacin. However, when added concomitantly to in vitro culture, these two compounds prime the synovial cell to synthesize a significantly greater amount of cAMP after exposure to PGE 2. This indicates that within the synovium, MCF may upregulate the synovial cell and prepare it for hormone (PGEz) exposure, thus enhancing the PGE 2 effect in inflammation. Such changes in hormone sensitivity (induced by MCF) are valid not only for PGE2, but for other hormones involved in bone resorption, as for example the parathyroid hormone 1-71].

4. Fibrotic and Repair Phase Concomitant to cartilage and bone destruction that develops throughout rheumatoid arthritis, attempts at tissue repair can be observed. Although there occurs newly synthesized proteogylcan, supporting evidence is at best weak in favor of newly synthesized collagen which retains its physiologic function. Nearly all of the newly synthesized collagen becomes scar tissue (fibrosis). The heterogeneous

403

Cytokines and Other Mediators in Rheumatoid Arthritis Table 6. Fibrotic and repair phase Mediator

Principal cell origin

Major biologiceffects

Reference

Fibroblast activating factor (FAF)

Lymphocyte

Fibroblast proliferation collagen synthesis

199

Connective tissue activating peptide (CTAP) Platelet-derived growth factor (PDGF) Epidermal growth factor (EGF)

Platelets

Connective tissue cell proliferation and activation glycosaminoglycansynthesis Connective tissue cell proliferation Decrease collagen and fibronectin synthesis and Type III to I collagen ratio

19, 211

PGEa

M0, synovialcells

IL-1 (MCF)

M0

IFN-y

Lymphocytes

Platelets Fibroblast

166 18, 137, 156

Increases collagen type III to 39, 181 I ratio Decreases total collagen production Increases collagen and 30 fibronectinsynthesisby synovial cells Decreases collagen synthesis 4

population of adherent cells cultured from the rheumatoid synovium also synthesize collagen and fibronectin which could reflect an attempt at repair in vivo. Exposure to M C F especially in the presence of indomethacin, stimulates overall protein synthesis. However, the synthesis of collagen types I and III and fibronectin appears to be stimulated preferentially. This stimulation is suppressed by the addition of exogenous PGE 2 [-39]. Taken together, PGE 2 inhibition of collagen synthesis and its induction of synovial cell collagenase may have a marked influence on the destructive phase of RA. Other factors affect markedly connective tissue metabolism (Table 6). A wellstudied factor is the connective tissue activating peptide (CTAP). This factor stimulates cell proliferation, glucose uptake, lactate output, and uronic acid (hyaluronate) synthesis [19, 211]. Other factors have been shown to stimulate collagen synthesis such as fibroblast activating factor (LAF) released from lymphocytes [199], other lymphokines [102, 143, 154], and monokines [30, 39, 70, 88, 97, 98, 188]. In contrast, epidermal growth factor (EGF), fibroblast growth factor (FGF), parathyroid hormone, 1,25(OH)2 D 3 [18, 137], IFN- 7 [4] as well as factors contained in blood mononuclear cell cultures decrease collagen synthesis [54, 101,120]. Prostaglandins [-155, 198] also inhibit collagen synthesis. These latter effects may be mediated by cyclic nucleotides which could not only alter the synthesis but also intracellular degradation of collagen [9, 28]. Finally, collagen synthesis is also under the control of ascorbic acid, /%adrenergic agonist, somatomedin, insulin, and bradykinin [11, 72, 136, 155]. The exact role of these agents, if any, in tissue repair of RA is not yet understood.

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Jean-Michael Dayer and Stephen Demczuk

Future Prospects In this review, we have attempted to show that a plethora of cellular mediators play a significant role in the development and perpetuation of RA. In understanding the etiology and pathophysiology of RA and other arthritic diseases, it is imperative to gain insight in the structural-functional interplay between such mediators. Although essential, their purification to homogeneity via classical biochemical procedures is too laborious, time consuming, and costly. For example, the physiologic concentrations of several cytokines vary from 10 - 1 2 to 10 -15 M. However, the recent advent of recombinant DNA technology has added a new powerful alternative to protein purification by alleviating many of those problems which have traditionally plagued the researcher purifying proteins existing in minute amounts. This new approach makes it now possible to in vitro synthesize cytokines involved in inflammation from purified cloned genetic material. Studies could then be undertaken on gene structure, regulation of expression, evolutionary relationships between biologically related inflammatory mediators (e. g., IL-1 and IL-2), and the physiological relevance of such mediators to the pathogenesis of RA. Due to the relative ease in molecular cloning and the wealth of information that soon follows, numerous groups have already initiated studies, whether intentionally or not, focusing on the mediators of RA. These include colony stimulating factor [13, 117]; the interleukins 1 [43, 205], 2 [46, 51, 118, 163, 184], and 3 [66, 212]; epidermal growth factor [78, 172]; plasminogen activator [50, 140, 144]; the interferons [45, 76, 77, 139, 144]; fibronectin [89]; C3 [56]; the proteins of the major histocompatibility complex [ 105]; and the osteoclast activating factor (OAF) [134]. Also of interest in the pathogenesis of RA are the acute phase reactant proteins. Their expression predominantly in the hepatocyte is complex, involving transcription and post-transcriptional regulation. A number of regulators such as hormones, fibrinolytic fragments, and interleukin l-like proteins (e. g., EP and LEM) have been shown to control their expression. Although many plasma acute phase proteins infiltrate and concentrate within the synovial fluid of the RA patient, their role in the pathogenesis and recovery of this disease is not fully understood. In cloning the genes which encode for these acute phase reactants, we can then begin to better assess their role in inflammatory diseases. The successful cloning or approaches to the cloning of several acute phase reactant genes has been reported for el-acid glycoprotein [157], serum amyloid A protein [180], cq-antitrypsin [107], ceruloplasmin [138], C-reactive protein [190, 203], fibrinogen [24, 25, 65], and haptoglobin [210]. Soon, all the known mediators of RA will be available from in vitro expressed, genetically cloned material. The information gathered from these genetic engineering studies, together with the continued research in cell biology, biochemistry (e. g., protein purification, sequencing, enzymology), and immunology (e. g., monoclonal antibodies and radioimmunoassays) will better our understanding in the pathogenesis of this crippling disease and facilitate its treatment. Acknowledgments. We highly appreciate the qualified secretarial assistance of Mrs M.-C. Seydoux.

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of human immune interferon cDNA and its expression in eukaryotic cells. Nucleic Acids Res 10: 2487 46. Devos R, Plaetinck G, Cheroutre H, Simons G, Degrave W, Tavernier J, Remaut E, Fiers W (1983) Molecular cloning of human interleukin 2 cDNA and its expression in E. coll. Nucleic Acids Res 11: 4307 47. Dinarello CA (1984) Interleukin-l. Rev Infect Dis 6:51 48. Duke O, Panayi GS, Janossy G, Poulter LW, Tidman N (1983) Analysis of T cell subsets in the peripheral blood and synovial fluid of patients with rheumatoid arthritis by mean of monoclonal antibodies. Ann Rheum Dis 42:357 49. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR (1978) Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet 2:117 50. Edlund T, Ny T, Ranby M, Heden LO, Palm G, Holmgren E, Josephson S (1983) Isolation ofcDNA sequences coding for a part of human tissue plasminogen activator. Proc Natl Acad Sci USA 80: 349 51. Efrat S, Pilo S, Kaempfer R (1982) Kinetics of induction and molecular size of mRNAs encoding human interleukin 2 and y-interferon. Nature 297:236 52. Egeland T, Mellbye OJ, Pahle JA (1981) Inflammatory synovial tissue mononuclear cells release leucocyte migration inhibition factor in antigen- and mitogen- free cultures. Ann Rheum Dis 40:388 53. Egeland T, Lea T, Mellbye OJ (1983) T-cell immunoregulatory functions in rheumatoid arthritis patients. Scand J Immunol 18:355 54. Elias JA, Rossman MD, Daniele RP (1982) Inhibition of human lung fibroblast growth by mononuclear cells. Am Rev Respir Dis 125:701 55. Ev~quoz V, Bettens F, Kristensen F, Trechsel U, Stadler BM, Dayer JM, Walz A, de Weck AL, Fleisch H (1984) (to be published) Stimulation of rabbit chondrocyte collagenase and prostaglandin E z production by interleukin 1. Eur J Immunol 56. Fey G, Domdey H, Wiebauer K, Whitehead AS, Odink K (1983) Structure and expression of the C3 gene. Springer Semin Immunopathol 6:119 57. Fischer S, Weber PC (1984) Prostaglandin 13 is formed in vivo in man after dietary eicosapentaenoic acid. Nature 307:165 58. Flower RJ, Blackwell GJ (1979) Anti-inflammatory steroids induce biosynthesis of a phospholipase A 2 inhibitor which presents prostaglandin generation. Nature 278:456 59. Folkman J, Haudenschild C (1980) Angiogenesis in vitro. Nature 288: 55l 60. Fontana A, Hengartner H, Weber E, Fehr K, Grob PJ, Cohen G (1982) Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int 2:49 61. Foon KA, Wahl SM, Oppenheim J J, Rosenstreich DL (1976) Serotonin-induced production of a monocyte chemotactie factor by human peripheral blood leukocytes. J. Immunol 117:1545 62. Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH (1980) Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 286:264 63. Freemont AJ, Jones CJP, Browley M, Andrews D (1983) Changes in vascular endothelium related to lymphocyte collections in diseased synovia. Arthritis Rheum 26:1427 64. Fuller GM, Ritchie DG (1982) A regulatory pathway for fibrinogen biosynthesis involving an indirect feedback loop. Ann NY Acad Sci 389:308 65. Fuller GM, Nickerson JM, Adams MA (1983) Translational and cotranslational events in fibrinogen synthesis. Ann NY Acad Sci 408:440 66. Fung MC, Hapel AJ, Ymer S, Cohen DR, Johnson RM, Campbell HD, Young IG (1984) Molecular cloning of cDNA for murine interleukin-3. Nature 307:233 67. Gatenby PA, Engelman EG (1981) Immunoregulation of the synovium of rheumatoid arthritis. Lancet 1:1348 68. Gemsa D (1981) Stimulation of prostaglandin E release from macrophages and possible role in the immune response. Lymphokines 4:335 69. Goetzl EJ, Kaplan AP (1983) Lipid and peptide mediators of inflammation. Fed Proc 42:3119 70. Goldberg RL, Parrott DP, Kaplan SR, Fuller GC (1980) Effect of gold sodium thiomalate on proliferation of human rheumatoid synovial cells and on collagen synthesis in tissue culture. Biochem Pharmacol 29:869 71. Goldring SR, Dayer JM, Krane SM (1984) Rheumatoid synovial cell hormone responses modulated by cell-cell interactions. Inflammation 8:107

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