IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 25

Immunologic Research 2003;28/1:25–37

The Function Role of GATA-3 in Th1 and Th2 Differentiation

Meixia Zhou1 Wenjun Ouyang*,2

Abstract

Key Words

GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6. GATA-3 regulates Th2 cytokine expression not only at the transcription level, such as directly binding to the promoters of the IL-5 and IL-13 gene, but also by the involvement in the remodeling of the chromatin structure and opening the IL-4 locus. As a master control, GATA-3 stabilizes the Th2 phenotype by two methods. First, GATA-3 shuts down Th1 development through the repression the IL-12 receptor β2-chain expression. Second, GATA-3 augments its own expression by a positive feedback autoregulation. In this article, we review the recent study of the function of GATA-3 in Th1 and Th2 differentiation.

Th1 Th2 GATA-3 Cytokines IFN-γ IL-4 Transcription factors

Introduction In response to different types of pathogen invasion, CD4+ T helper cells play central roles in the guidance of the organism to the development of either cellular or humoral effector pathway to clear the infections. T helper cells can be classified into two distinct subsets based on their different cytokine production profiles (1). T helper 1 (Th1) cells produce interferon-gamma (IFN-γ), interleukin (IL)-2, and tumor-necrosis factor (TNF), whereas T

Wenjun Ouyang Department of Immunology Genentech, Inc. 1 DNA Way South San Francisco, CA 94080 E-mail: [email protected]

© 2003 Humana Press Inc. 0257–277X/03/ 28/1:25–37/$25.00

1

Department of Pathology, Washington University School of Medicine, St. Louis, MO 2 Department of Immunology, Genentech, Inc., South San Francisco, CA

helper 2 (Th2) cells produce IL-4, IL-5, IL-13, and IL-6. Th1 and Th2 cells exercise different immune responses. Th1 cells mediate the elimination of intracellular pathogens. IFN-γ made by the Th1 subset is the major mediator of a specific immune response to intracellular pathogens such as Leishmania major and Leishmania monocytogenes. IFN-γ can promote macrophages to express iNOS and other factors to eliminate intracellular pathogens (2). IFN-γ is also required for clearing many

25

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 26

other intracellular pathogens, such as bacteria, fungi, and protozoa (3). Another function of IFN-γ is to the deliver the isotype switch signal for B cells to produce IgG2a antibody. Knockout mice in which the IFN-γ or IFN-γ receptor genes have been disrupted show several immunologic defects, including increased susceptibility to infection with intracellular microbes, reduced production of nitric oxide by macrophages, reduced serum levels of IgG2a, and defective natural-killer (NK) cell function (4). Therefore, IFN-γ protects against many viral and intracellular pathogens through pleiotropic effects. On the other hand, Th2 cells mediate the clearance of large extracellular pathogens such as helminthes. Th2 cells are also involved in allergy reactions that can cause the pathophysiological outcome of asthma, urticartia, and other forms of atopy (5,6). IL-4 produced by the Th2 subset is a major regulator of IgEmediated and mast cell/eosinophil-mediated immune reaction. IL-4 is required for the switching of B cells to produce the IgE isotype. IL-4 is also a growth factor for mast cells and Th2 cells. IL-4-deficient mice were not able to mount a Th2 response or produce IL-5 or IL-13. In addition, these mice had dramatically decreased serum IgG1 and IgE levels (7,8). Thus, IL-4 plays a critical role in IgEand eosinophil-mediated inflammatory reactions and Th2 subset differentiation. Since the landmark demonstration of Th1 and Th2 cells by Mossman and Coffman, major progress in both cellular and molecular mechanisms by which the two distinct populations develop has been made. Both the T cell receptor (TCR) signal and cytokine signals are required for T-helper-cell differentiation. TCR-specific transcription factors such as nuclear factor of activated T cells (NFATs) and nuclear factor κB (NFκB) and cytokine specific transcription factors, such as STAT4 and

26

STAT6, play key roles in this process. In addition, Th1-specific and Th2-specific transcription factors such as T-bet and GATA-3 are also required. Here, we will review recent progress in understanding the role of GATA-3 during the T-helper-cell differentiation. The Role of GATA-3 in Th2 Development General Aspects of Th2 Development Interleukin-4 is the critical cytokine that drives Th2 development (9,10). Although several types of cell, such as mast cells, basophils, and NK1.1+/CD3+ T cells, have been shown to secrete IL-4, the initial source of IL-4-driven Th2 development in vivo is still unclear. IL-4 receptor is a heterodimer composed of the specific IL-4Rα subunit and the common γ-subunit (11). The cytoplasmic domains of IL-4R are associated with Jak1 and Jak3. Upon binding to its receptor, IL-4 can initiate the phosphorylation and activation of Jak1 and Jak3, which, in turn, phosphorylate IL-4R subunits (12,13). Phosphorylated IL-4 receptors can further recruit and activate a Stat family member, Stat6. Activated Stat6 will form a dimer, which enables it to enter the nucleus and initiate the transcription of downstream Th2-specific genes. Thus, Stat6 was considered to be the central mediator of the IL-4 signal involved in Th2 development (14,15). The importance of IL-4 and Stat6 in Th2 differentiation has been demonstrated by the generation of IL-4 or Stat6 target-specific deficient mice. CD4 T cells from IL-4-deficient mice have a defect to mount a Th2 response or produce IL-5 and IL-13 after in vivo challenge (7,8). Similarly, in Stat6-deficient mice, Th2 differentiation was blocked, and IgE titers in response to Nippostrongylus brasiliensis had been dramatically decreased (16,17). In the past few years, in order to further dissect the IL-4 signaling pathway and

Zhou and Ouyang

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 27

molecular mechanism of Th2 development, people focused on looking for factors downstream of Stat6 that are directly involved in the initiation of the transcription of the Th2specific genes. Identification of GATA-3 in Th2 Differentiation A key transcription factor identified as important for Th2 development is GATA-3. GATA-3 is a zinc-finger transcription factor and belongs to the GATA family transcription factors that bind to the consensus DNA sequence, WGATAR (W = A/T; R = A/G). There are six members of the GATA gene family that have been cloned in mammals, GATA-1 to GATA-6, which may be classified as hematopoietic (GATA-1 to GATA-3) or nonhematopoietic (GATA-4 to GATA-6) (18). GATA-3 has been shown to be expressed in hematopoietic cells, in the developing kidney, and in the nervous system (19,20). Importantly, by using the knockout strategy, GATA-3 has been demonstrated to be essential for thymocyte development as well as for embryonic development. Mice containing homozygous null mutations of the GATA-3 gene die on embryonic d 12 (19). Using RAG-2 blastcyst reconstitution, Leiden and his colleagues showed an arrest of thymocyte development at the double-negative stage (20). GATA-3 has long been speculated to play important roles in regulating cytokine gene expressions in T cells. Initially, GATA-3 was proposed to regulate IFN-γ gene expression in Th1 cells. However, a subsequent study found that GATA-3 was primarily restricted expressed in Th2 cells (21). Ray and colleagues demonstrated the critical role of GATA-3 binding site in the IL-5 promoter (22). They further indicated that GATA-3 was differentially expressed in Th2 cells and involved in regulating IL-5 gene expression (23). The essen-

Role of GATA-3 in Th1 and Th2 Differentiation

tial role of GATA-3 for Th2 development was first established by Zheng and Flavell (21). Using representational difference analysis (RDA), they found that GATA-3 was upregulated selectively during the differentiation of Th2 cells but not Th1 cells. When stably transfected Th2 clones with antisense GATA-3, the reduced GATA-3 protein levels in the transfected cells were associated with the inhibition of the expression of all Th2 cytokine genes (21). In GATA-3 transgenic mice system, elevated GATA-3 in CD4 T cells caused Th2 cytokine gene expression in T cells. In order to further dissect the function of GATA-3 during primary T-cell differentiation, we forced expression of GATA-3 by retroviral infection, and thereby reversed the phenotype differentiation of the developing Th1 cells. Instead of IFN-γ production, these “Th1” cells produced all Th2 cytokines, including IL-4, IL-5, IL-13, IL-10, and IL-6 (24). Intriguingly, the development of the Th2 phenotype is independent of IL-4, because the IL-4-deficient T cells primed under the Th1 condition also switched to the Th2 phenotype after they were introduced to GATA-3 by the retrovirus. We further demonstrated that the Th2-specific GATA-3 expression was Stat6 dependent because T cells from Stat6deficient mice failed to upregulate its GATA3 after priming under the Th2 condition. However, the augmented level of GATA-3 can bypass the requirement of Stat6 for Th2 development (25), suggesting that GATA-3, acting as a master switch, bridges the IL-4 signaling to the downstream genes. Regulation of Cytokine Genes by GATA-3 IL-4 Interleukin-4 gene regulation at the promoter level has been extensively studied (26–29). Wenner et al. generated a series of

27

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 28

murine transgenic lines harboring the luciferase gene driven by regions of the IL-4 promoter in the DO11.10 TCR transgenic background. The IL-4 promoter –741 to +60 bp region allowed, on average, a 40-fold higher inducible reporter activity in Th2 cells than in Th1 cells. However, despite the presence of GATA-binding sites in the promoter, the overall expression of luciferase was significantly lower than the endogenous IL-4 gene at the messenger level (30). Zheng et al. proposed that GATA-3 could directly drive the transcription of the IL-4 gene through this 800-bp promoter region (21). Nevertheless, this transcriptional activity has not been directly mapped to this region in a more detailed promoter study (31). It has also been found that the antisense of GATA-3 can inhibit IL-5 but not IL-4 promoter activation, which argues that although GATA-3 directly transactivates the IL-5 promoter, it has significantly less activity in the IL-4 promoter (32). Therefore, GATA-3 might be permissive but not sufficient for full induction of IL-4 gene and may act through GATA-3-binding elements surrounding the IL-4/IL-13 gene locus. Consistent with this idea, several regions with GATA-3-dependent enhancer activity were identified within the IL-4/IL-13 locus, which suggests that GATA-3 could regulate IL-4 gene expression at distant loci (31). It has long been hypothesized that cytokine gene regulation may also be involved in remodeling the gene locus at the chromatin level. Agarwal et al. mapped Th2-specific DNase I hypersensitivity (HS) sites in the IL-4 gene locus (33). They identified five HS sites within a BamHI fragment containing the IL-4 gene. Among them, HS site IV is present in both Th1 and Th2 cells. The other HS sites are Th2 specific and are not detected in Th1 cells. We examined whether GATA-3 might play direct role in opening the IL-4 locus. Upon retroviral infection of Th2 cells from Stat6 –/– mice

28

with GATA-3, we found that all of these hypersensitivity sites were induced by the forcible GATA-3 expression, which implied that GATA-3 rather than Stat6 controlled the accessibility of the IL-4 locus (25). In concurrence with our results, Lee et al. observed that GATA-3 could induce these DNase I hypersensitivity sites in wild-type developing Th1 cells (34). Moreover, by using a similar approach, Takemoto et al. showed that forcible expression of GATA-3 also induced the DNase I hypersensitivity sites in the IL-13 gene and in the newly identified intergenic conserved noncoding sequence 1 (CNS-1) region (35). CNS-1 is located between IL-4 and IL-13, and is highly conserved in mammals. It has been shown that CNS-1 is crucial for the expression for IL-4, IL-13, and IL-5 genes (36). Direct evidence that GATA-3 participates in IL-4 gene regulation has come from the in vivo chromatin immunoprecipitation (CHIP) experiments. Agarwal et al. showed that GATA-3 in Th2 cells could bind to a 3′-region, enhancer of the IL-4 gene in vivo. To search for distal regulatory elements that might be important for GATA-3 involved IL-4, Lee and his colleagues used a transgenic approach to rebuild the IL-4 minilocus with a reporter gene. This minilocus includes DNAase I hypersensitivity sites, an intronic enhancer, elements in the 3′ region, and the CNS-1 region (37). Their data demonstrated that the elements in the 3′ region showed weaker enhancer activity, but rather rendered IL-4 gene the Th2 specificity. Other elements mainly contributed to the T-cell specificity and enhancer function. The presence of all these elements and the formation of the minilocus are critically important for the strong and Th2-specific expression of the IL-4 gene. Furthermore, GATA-3 could largely augment the IL-4 promoter activity through all of these elements (37). In conclusion, GATA-3 is necessary for the IL-4 gene Th2-specific expression. However, the

Zhou and Ouyang

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 29

enhanced and TCR-controlled IL-4 expression required the cooperation of GATA-3 with other transcription factors. IL-5 The recognition that GATA-3 might be involved in IL-5 gene regulation preceded the discovery of the role of GATA-3 in Th2 development. By using electrophoretic mobility shift assay (EMSA) and mutation studies, Ray and her collages first demonstrated that a GATA-3-binding site located in –70 to –59 of the IL-5 promoter is required for the activation of the promoter (23). When they ectopically expressed GATA-3 in a B cell line M12, they found that GATA-3 was sufficient to drive IL-5 but not IL-4 gene expression. Moreover, in Th2 cells, antisense GATA-3 RNA inhibited IL-5 but not IL-4 promoter activation. The induction of IL-5 gene expression by GATA-3 involved high-affinity binding of GATA-3 to an inverted GATA repeat in the IL-5 promoter (32). In conclusion, GATA-3 might be directly involved in the initiation of transcription machinery on the IL-5 promoter. More recently, a potential negative regulatory the GATA-binding site has been identified in the human IL-5 promoter, suggesting a more complex role of GATA-3 in IL-5 gene regulation (38). IL-13 Interleukin-13 is another important Th2 cytokine. Together with IL-4, IL-13 can enhance the production of IgE and trigger the airway remodeling process (39,40). The transcription regulation of IL-13 has not been extensively studied. Zheng et al. has shown that overexpression of an antisense GATA-3 in a Th2 clone, D10, inhibited all of the Th2 cytokine gene production, including IL-13 (21). Forced expression of GATA-3 in developing Th1 cells augments the level of Th2 cytokine genes, including IL-13 in a IL-4- and Stat6 independent manner, suggesting that

Role of GATA-3 in Th1 and Th2 Differentiation

GATA-3 might be involved in IL-13 gene regulation (25). Recently, Kishikawa et al. have identified and cloned a minimal inducible and cell-type-specific promoter of the murine IL-13 gene. By performing EMSA and supershift experiments, they found that GATA-3 could bind to a GATA site located at –95 of the promotor. This site contributes to cell-typespecific activity of the minimal IL-13 promoter (41). Therefore, GATA-3 plays important roles in the regulation of IL-13 gene expression. Other Th2-Specific Transcription Factors and Their Roles in Th2 Development Several transcription factors have been identified to involve in Th2 development, including Jun-B, NFAT, and c-Maf. These transcription factors are either selectively expressed in Th2 cells or functioning in regulation of Th2 cytokines in a cell-typespecific manner. NFAT family transcription factors are activated by the stimulation of receptors coupled to calcium mobilization, and their activation is blocked by cyclosporin A (CsA) and FK506 (42). NFAT proteins consist of two transactivation domains: one at the amino terminus and one at the carboxy terminus, a regulatory domain, and a DNA binding domain in the middle. Rao and colleagues recently demonstrated the potential cooperation of GATA-3 and NFAT in the regulation of Th2 cytokines. They identified an inducible, cyclosporin A-sensitive enhancer located 3′ of the IL-4 gene by DNase hypersensitivity analysis. They further presented in vivo evidence that GATA-3 and NFATc could bind to this site specifically in Th2 cells (43). There are three known NFAT proteins expressed in both Th1 and Th2 cells and they can transactivate the cytokine gene promoter in vitro (42). The consensus NFAT-binding sequence is (T/A)GGAAAA(A/T/C)N, which has been found in many cytokine gene pro-

29

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 30

moter regions, includes IL-2, IL-4, IL-5, granulocyte and monocyte colony-stimulating factor (GM-CSF), and IFN-γ. However, the phenotypes of mice deficient in either NFATp or NFATc suggested these proteins might play a Th-selective and reciprocal role in the regulation of Th1 and Th2 development (44). In NFATc-deficient mice, IL-4 production was severely reduced in lymphocytes (45,46). In contrast, IL-4 production was enhanced in NAFTp-deficient mice (47,48). Furthermore, in NFATp and NFAT4 double-deficient mice, the Th2 compartment was extreme and selectively activated, and NFATc was constitutively localized in the nuclei (47). These data suggested a repressor role for NFATp and NFAT4 and a positive role for NFATc in controlling Th2 development. A NFAT interacting protein (NIP45) was recently cloned and showed to synergize with NFATp and c-Maf to active the IL-4 promoter in the transient reporter assay and also to cooperate with c-Maf to induce endogenous IL-4 expression in M12 B lymphomas (49). Several kinases have been shown to regulate the nuclear export of NFAT, including GSK3 and JNK (Jun N-terminal kinase) (44). Dong et al. recently reported that in JNK1deficient mice, Th cells were hyperresponsive to TCR stimulation and preferentially become Th2 phenotype and are accompanied by constitutive nuclear localization of NFATc, which is similar to that of mice lacking NFATp (50). However, the negative regulation of NFAT by the JNK pathway is only reported with NFAT4, but not NFATc (51). Therefore, mechanisms causing the JNK1 –/– phenotype need to be further determined. JunB is a member of the AP-1 family and is selectively induced in Th2 cells, but not in Th1 cells (52,53). In JunB transgenic mice, several Th2 cytokine expression levels were increased even in developing Th1 cells. JunB

30

could also synergize with c-Maf to activate an IL-4 promoter luciferase reporter (52). In the same study, JunB was shown to be activated by JNK mitogen-activated protein (MAP) kinases. However, previous results showed that JNK kinases were selectively activated in Th1 cells other than Th2 cells. This controversy needs to be further addressed in the future. c-Maf is a basic region/leucine zipper transcription factor that belongs to the subfamily of the AP-1/CREB/ATF protein. Ho et al. (54) have demonstrated that c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. Ectopic expression of c-Maf transactivates the IL-4 promoter (54). It has been shown by in vivo footprinting that c-Maf can bind MARE (c-Maf binding site) in the proximal IL-4 promoter, by which c-Maf may exert its regulation of the IL-4 gene. Analysis of c-Maf transgenic mice demonstrates that c-Maf can promote Th2 differentiation by IL-4-dependent mechanisms and can attenuate Th1 differentiation (in term of IFN-γ production) by Th2 cytokineindependent mechanisms (55). Recently, Kim et al. have shown that c-Maf –/– T cells were markedly deficient in IL-4 production; however, the levels of other Th2 cytokines in these T cells remain normal (56). Therefore, c-Maf has a critical function in IL-4 gene transcription but not other Th2 cytokine genes. The Role of GATA-3 in Th1 Development General Aspects of Th1 Development Interleukin-12 is a critical cytokine for Th1 development in both the murine and human system (57–61). IL-12, composed of p40 and p35 subunits, is largely induced in macrophage and dendritic cells (62). The effects of IL-12 are mediated through a heterodimer IL-12 recepters, consisting of β1- and β2-subunits

Zhou and Ouyang

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 31

(63,64). By studying the expression of the IL-12 receptor β2 chain, Szabo showed that IL-12Rβ2 is expressed in Th1 cells but not in Th2 cells, which explains the inability of IL-12 to reverse early Th2 differentiation (65) in murine T cells. Upon receptor binding by IL-12, the associated Jak2 and Tyk2 become activated and, in turn, phosphorylate tyrosine residues in the cytoplasmic tails of β1- and β2-subunits (66). Phosphorylated β1- and β2-subunits thereby provide docking sites for Stat4. Upon docking to the receptor tails, Stat4 is phosphorylated and forms homodimers or heterodimers with Stat1/Stat3. Activated Stat4 dimers then can enter nucleus and exert their functions on downstream genes (67). T cells from Stat4-deficient mice have a defect in Th1 development after being treated with IL-12 (68). Th1-Specific Transcription Factors and Their Roles in Th1 Development Several transcription factors preferentially expressed in Th1 cells have been identified. We found that ERM, an Ets family member, is selectively expressed in Th1 cells. ERM has been shown to be induced by IL-12 through Stat4 activation (69). However, overexpression of ERM gene did not induce IFN-γ production. Therefore, the functions of ERM in Th1 cells require further investigation. Szabo recently identified another Th1-specific transcription factor, T-bet. Retroviral transduction of T-bet into unskewed CD4 T cells, developing Th2 cells and fully differentiated Th2 cells, increases IFN-γ production (70). T-betdeficient mice have severely impaired production of IFN-γ and increased production of Th2 cytokines (71). These mice are more susceptible to intracellular parasites’ infection and are completely protected from the development of autoimmune diseases such as IBD and SLE. However, they are highly susceptible to asthma (S.J. Szabo et al., unpublished

Role of GATA-3 in Th1 and Th2 Differentiation

data; M.F. Neurath et al., unpublished data; S. Peng et al., unpublished data). However, Mullen et al. recently showed that T-bet was a downstream factor of IFN-γ and the Stat1 pathway and might be involved in regulation IL-12 receptor β2 gene expression (72). Whether T-bet directly participates in IFN-γ gene regulation or T-bet influences Th1 development through the regulation of IL-12 signaling components is still unclear. GATA-3 Inhibits Th1 Development Through Intrinsic Mechanism The potential negative role of GATA-3 in Th1 development was first suggested in our examination of the expression patterns during Th1 development. We noted that GATA-3 was actively repressed by IL-12 and the IFN-γ signaling pathway during Th1 differentiation, implying a possible negative function of GATA-3 in Th1 development (24). To test this, we introduced GATA-3 into T cells by retroviral infection during Th1 development. GATA-3-expressing T cells did not produce IFN-γ and other Th1 cytokines, whereas they expressed IL-4, IL-5, IL-13, and other Th2 cytokines. The block of Th1 development was not simply the result of the induction of Th2 cytokines, because we observed similar inhibition in both IL-4-deficient and Stat6deficient T cells. Furthermore, in a mixing experiment, where GATA-3 transfected and control T cells were cultured together and exposed to the same environment stimulus, only the GATA-3 expression T cells were blocked for IFN-γ expression, indicating that GATA-3 inhibited Th1 development through an intrinsic mechanism. The following study further demonstrated the inhibition correlated with the repression of the IL-12 receptor β2-chain expression in these cells (24). However, how GATA-3, a transcription activator, plays negative role in certain stage of

31

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 32

cell differentiation need to be addressed in the future. The Regulation of GATA-3 in Th1 and Th2 Development The demonstration of GATA-3 as a Th2specific transcription factor implied that cytokines involved in Th1 and Th2 differentiation might also directly regulate GATA-3 expression. We first demonstrated that the Th2-specific induction of GATA-3 was accomplished by two distinct mechanisms. First, IL-4 through the activation of Stat6 augmented GATA-3 expression. Second, the complete repression of GATA-3 production in Th1 cells required both IL-12 and IFN-γ signaling dependent on the activation of Stat4 and Stat1, respectively (24). TCR signaling was necessary for GATA-3 expression, especially signal delivery by CD28 (73). Other cytokines, such as IL-1, have been shown to activate the cAMP signaling pathway, which will invoke the p38 activation and phosphorylate GATA-3 (74). The transforming growth factor (TGF)-β pathway has also been demonstrated to block Th2 development through the repression of GATA-3 expression (75,76). However, despite its negative role, one of the TGF-β downstream factors, Samd3, has been shown to directly interact with GATA-3 and cooperate synergistically to regulate transcription from the IL-5 promoter in a TGF-β dependent manner (77). In conclusion, many other cytokines that influence Th1/Th2 balance may also directly or indirectly control the expression of GATA-3. We will focus on intracellular factors that may regulate GATA-3 expression or function in the following discussion. GATA-3 Can Autoregulate Its Own Expression When analyzing GATA-3 expression in retroviral infected T cells by Northern blot,

32

we observed that a small amount of retroviral GATA-3 messenger can induce strong expression of endogenous GATA-3 in wild-type, IL-4 –/–, and Stat6 –/– Th1 cells (25). The striking finding of the endogenous GATA-3 in these cells indicated that GATA-3 could regulate its own expression independent of the IL-4 signal and Stat6 activation. This phenomenon has been confirmed in three other studies (78–80). Ranganath et al. further showed that endogenous GATA-3 expression could be induced not only by GATA-3 but also by other GATA family members, such as GATA-1, GATA-3, and GATA-4, in Stat6 –/– T cells. The GATA-3 protein contains two transactivation domains, TA1 and TA2, and also zinc-finger regions, N-finger and C-finger. The study of GATA-3 mutation showed that retroviral expression of the GATA-3 mutants ∆TA1, ∆Nf , and ∆Cf failed to activate expression of the endogeneous GATA-3, whereas ∆TA2 the GATA-3 mutant showed some weak activation of the endogenous GATA-3 gene. Therefore, TA1, N-finger, and C-finger are required for GATA-3 autoactivation, whereas TA2 might be dispensable for this activity (80). Autoactivation seems to be a common paradigm in stabilizing development programs involving transcription factors. For example, autoactivation of Pit-1and GATA-2 occurs in the developing pituitary after their transient induction by FGF-8 and BMP2/4, stabilizing cellular commitment to expression of specific pituitary hormones (81). In erythroid lineage cells, GATA-1 gene autoactivation is believed to provide a mechanism for progressive accumulation of GATA-1 protein and to promote erythroid differentiation (82). Therefore, our demonstration that GATA-3 exhibits positive regulation fits well into a recognized pattern of mechanisms for maintaining cell fate commitment. In naïve T cells, the level of GATA-3

Zhou and Ouyang

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 33

expression is very low. Once the cells get IL-4 signaling through SATA 6, GATA-3 expression is promoted. The small amount of GATA-3 expression can then autoactivate its own expression. Once the autoactivation loop is turned on, the cell with a high GATA-3 expression level will promote Th2 development and inhibit Th1 development, and quickly stabilize Th2 phenotype. GATA-3’s Function Can Be Regulated by Other Factors Nuclear factor kappa B (NF-κB) is a transcription factor activated by TCR engagement. Ray and colleagues recently found that in NF-κB p50-deficient mice, CD4+ T cells under the Th2 priming condition failed to induce GATA-3 expression but maintained unimpaired T-bet and IFN-γ expression under the Th1 differentiation condition (83). This result demonstrated that NF-κB p50 played crucial role in GATA-3 regulation. Friend of GATA-1 (FOG-1) was initially cloned by yeast two hybrid screening for the interaction with the N-finger of GATA-1 (84). FOG-1 is distinctive for its nine widely spaced zinc fingers, which could involve in protein–DNA binding and also protein– protein interaction. Mice lacking FOG-1 die between E10.5 and E12.5 with severe anemia. Analysis of FOG-1–/– embryos indicates that FOG-1 serves as a complex cofactor that acts through both GATA-dependent and GATAindependent mechanisms (85). Several other FOG family members was subsequently identified, including U-shaped (Ush) in Drosophila (86) and FOG-2 in mammals (87,88). Among known FOG family members, only FOG-1 is expressed in hematopoietic cells. We recently investigated the potential function of FOG-1 in regulate GATA-3’s activity (79). We observed that FOG-1 could repress GATA-3-dependent activation of the IL-5 pro-

Role of GATA-3 in Th1 and Th2 Differentiation

moter in T cells. Also, FOG-1 overexpression during primary activation of naive T cells inhibited Th2 development in CD4+ T cells. When we retrovirally coinfected both FOG-1 and GATA-3 into developing Th1 cells with a Stat6-deficient background, we found that FOG-1 fully repressed GATA-3-dependent Th2 development and GATA-3 autoactivation, but not Stat6-dependent induction of GATA3 in wild-type Th2 cells. When FOG-1 was overexpressed in fully developed Th2 cells, it did not change Th2 cytokine profiles. Our result suggests that FOG-1 overexpression repressed development of Th2 cells from naive T cells but did not reverse the phenotype of fully committed Th2 cells. Because of the expression of FOG-1 in naive T cells, FOG-1 thus might function as a brake to prevent GATA-3 autoactivation and maintain T cells as unskewed naive phenotype in normal condition (79). ROG (repressor of GATA-3) was another GATA interact factor recently cloned by using the zinc-finger domain of human GATA-3 (corresponding to amino residue 96–444) as a bait to screen the Th2 yeast prey library. ROG is a lymphoid-specific gene and is quickly induced in Th cells upon stimulation with anti-CD3. ROG is able to repress the GATA-3-induced gene transcription in vitro. However, ROG is expressed in both Th1 and Th2 cells, and ROGmediated cytokine inhibition is not restricted to Th2 cytokines such as IL-4 and IL-5, but also includes Th1 cytokines such as IFN-γ. Inhibiting GATA-3 is not the sole function of ROG. ROG may regulate overall T-cell activation through repressing IL-4 and IL-5 expression mediated by GATA-3 inhibition and repressing IFN-γ mediated by some unknown factors in Th1 cells (89). Bcl-6 and CIITA are two potential inhibitors that might block Th2 development. Mice with a disrupted Bcl-6 gene developed

33

IR28/1,03,25-38,14pgs

7/25/03 9:39 AM

Page 34

myocarditis and pulmonary vasculitis, had no germinal centers, and had increased expression of T-helper-cell type 2 cytokines (90). However, the repression of Th2 development by Bcl-6 might not occur through a Stat6- and GATA-3-dependent pathway (91), rather it might occur through a mechanism involving the regulation of chemokine expression and T-cell homing (92). Although in CIITAdeficient and MHC class II gene I-E transgenic T cells, Th2 cytokines production was increased (93), the mechanism of this function of CIITA is still unclear.

Concluding Remarks In conclusion, GATA-3 plays central role in control the Th1 and Th2 differentiation. Recently, several group reported GATA-3 expression was significantly increased in asthmatic airways when compared with control subjects (94). Interestingly, two groups using murine asthma model demonstrated that inhibiting the expression of GATA-3 or blocking the function of GATA-3 could attenuate the development of disease, indicating that GATA-3 is a potential therapeutical target (95,96).

References 1. Mosmann TR, Cherwinski H, Bond HW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348–2357. 2. Stenger S, Thuring H, Rollinghoff M, Bogdan C: Tissue expression of inducible nitric oxide synthase is closely associated with resistance to Leishmania major. J Exp Med 1994;180(3):783–793. 3. Reiner SL, Seder RA: T helper cell differentiation in immune response. Curr Opin Immunol 1995;7(3):360–366. 4. Farrar MA,Schreiber RD:The molecular cell biology of interferongamma and its receptor. Annu Rev Immunol 1993;11:571–611. 5. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, et al.: Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326(5):298–304. 6. Erb KJ, Le Gros G: The role of Th2 type CD4+ T cells and Th2 type CD8+ T cells in asthma. Immunol Cell Biol 1996;74(2):206–208. 7. Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Kohler G: Disruption of the murine IL-4 gene blocks Th2 cytokine

34

8.

9.

10.

11.

12.

13.

responses. Nature 1993;362(6417): 245–248. Kuhn R, Rajewsky K, Muller W: Generation and analysis of interleukin-4 deficient mice. Science 1991;254(5032):707–710. Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature 1996;383 (6603):787–793. Seder RA, Paul WE: Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994;12:635–673. Mosley B, Beckmann MP, March CJ, Idzerda RL, Gimpel SD, VandenBos T, et al.: The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell 1989;59(2):335–348. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, et al.: Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 1994;266(5187):1045–1047. Yin T, Tsang ML, Yang YC: JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes. J Biol Chem 1994;269(43): 26,614–26,617.

14. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL: An interleukin-4-induced transcription factor: IL-4 Stat. Science 1994;265(5179):1701–1706. 15. Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, et al.: Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol 1995;15(6):3336–3343. 16. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al.: Lack of IL-4induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996; 380(6575):630–633. 17. Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S: Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol 1996;157(8): 3220–3222. 18. Orkin SH: Hematopoiesis: how does it happen? Curr Opin Cell Biol 1995;7(6):870–877. 19. Pandolfi PP, Roth ME, Karis A, Leonard MW, Dzierzak E, Grosveld FG, et al.: Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver

Zhou and Ouyang

IR28/1,03,25-38,14pgs

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

7/25/03 9:39 AM

haematopoiesis. Nat Genet 1995; 11:40–44. Ting CN, Olson MC, Barton KP, Leiden JM: Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 1996;384:474–478. Zheng W., Flavell RA: The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997;89:587–596. Siegel MD, Zhang DH, Ray P, Ray A: Activation of the interleukin-5 promoter by cAMP in murine EL-4 cells requires the GATA-3 and CLE0 elements. J Biol Chem 1995;270(41):24,548–24,555. Zhang DH, Cohn L, Ray P, Bottomly K, Ray A: Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 1997;272: 21,597–21,603. Ouyang W., Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha W, et al.: Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 1998;9:745–755. Ouyang W., Lohning M, Gao M, Assenmacher M, Ranganath M, Radbruch A, et al.: Stat6independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 2000;12:27–37. Li-Weber M., Davydov IV, Krafft H, Krammer PH: The role of NF-Y and IRF-2 in the regulation of human IL-4 gene expression. J Immunol 1994;153:4122–4133. Szabo SJ, Gold JS, Murphy TL, Murphy KM: Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc [published erratum appears in Mol Cell Biol 1993; 13(9):5928]. Mol Cell Biol 1993; 13:4793–4805. Rooney JW, Hoey T, Glimcher LH: Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. Immunity 1995;2:473–483. Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli

Role of GATA-3 in Th1 and Th2 Differentiation

Page 35

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

H, et al.: Signaling and transcription in T helper development. Annu Rev Immunol 2000;18:451–494. Wenner CA, Szabo SJ, Murphy KM: Identification of IL-4 promoter elements conferring Th2restricted expression during T helper cell subset development. J Immunol 1997;158:765–773. Ranganath S, Ouyang W, Bhattarcharya D, Sha WC, Grupe A, Peltz G, et al.: GATA-3-dependent enhancer activity in IL-4 gene regulation. J Immunol 1998;161: 3822–3826. Zhang DH, Yang L, Ray A: Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3. J Immunol 1998;161:3817–3821. Agarwal S, Rao A: Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 1998;9:765–775. Lee HU, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O’Garra A, et al.: GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med 2000;192(1):105–115. Takemoto N, Kamogawa Y, Jun Lee H, Kurata H, Arai KI, O’Garra A, et al.: Chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster. J Immunol 2000;165:6687–6691. Loots GG, Locksley RM, Blankespoor CM, Wang ZE, Miller W, Rubin EM, et al.: Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 2000;288(5463):136–140. Lee GR, Fields PE, Flavell RA: Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 2001;14(4):447–459. Schwenger GT, Fournier R, Kok CC, Mordvinov VA, Yeoman D, Sanderson CJ: GATA-3 has dual regulatory functions in human interleukin-5 transcription. J Biol Chem 2001;276(51):48,502–48,509. Defrance T, Carayon P, Billian G, Guillemot JC, Minty A, Caput D, et al.: Interleukin 13 is a B cell stim-

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

ulating factor. J Exp Med 1994; 179(1):135–143. Emson CL, Bell SE, Jones A, Wisden W, McKenzie AN: Interleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13. J Exp Med 1998;188(2):399–404. Kishikawa H, Sun J, Choi A, Miaw SC, Ho IC: The cell typespecific expression of the murine IL-13 gene is regulated by GATA-3. J Immunol 2001;167(8): 4414–4420. Rao A., Luo C, Hogan PG: Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997;15: 707–747. Agarwal S, Avni O, Rao A: Celltype-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 2000;12(6):643–652. Glimcher LH, Singh H: Transcription factors in lymphocyte development—T and B cells get together. Cell 1999;96:13–23. Ranger AM, Hodge MR, Gravallese EM, Oukka M, Davidson L,Alt FW, et al.: Delayed lymphoid repopulation with defects in IL-4driven responses produced by inactivation of NF-ATc. Immunity 1998;8:125–134. Yoshida H, Nishina H, Takimoto H, Marengere LE, Wakeham AC, Bouchard D, et al.: The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production. Immunity 1998;8:115–124. Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, Glimcher LH: Hyperproliferation and dysregulation of IL-4 expression in NF-ATpdeficient mice. Immunity 1996;4: 397–405. Xanthoudakis S., Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT, et al.: An enhanced immune response in mice lacking the transcription factor NFAT1 [published erratum appears in Science 1996; 273(5280):1325]. Science 1996; 272:892–895. Hodge MR, Chun HJ, Rengarajan J, Alt A, Lieberson R, Glimcher

35

IR28/1,03,25-38,14pgs

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

36

7/25/03 9:39 AM

LH. NF-AT-driven interleukin-4 transcription potentiated by NIP45. Science 1996;274:1903–1905. Dong C,Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA: Defective T cell differentiation in the absence of Jnk1. Science 1998; 282:2092–2095. Chow CW, Rincon M, Cavanagh J, Dickens M, Davis RJ: Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 1997;278: 1638–1641. Li B, Tournier C, Davis RJ, Flavell RA: Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 1999;18:420–432. Rincon M, Derijard B, Chow CW, Davis RJ, Flavell RA: Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector Th1 and Th2 cells. Genes Function 1997;1:51–68. Ho IC, Hodge MR, Rooney JW, Glimcher LH:The proto-oncogene c-maf is responsible for tissuespecific expression of interleukin-4. Cell 1996;85(7):973–983. Ho IC, Lo D, Glimcher LH: c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4dependent and -independent mechanisms. J Exp Med 1998; 188(10):1859–1866. Kim JI, Ho IC, Grusby MJ, Glimcher LH: The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 1999;10(6): 745–751. Hsieh CS, Macatonia SE,Tripp CS, Wolf SF, O′Garra A, Murphy KM: Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 1993;260(5107):547–549. Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, Ferrante J, et al.: IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 1996;4(5): 471–481. Piccotti JR, Li K, Chan SY, Ferrante J, Magram J, Eichwald EJ,

60.

61.

62.

63.

64.

65.

66.

67.

68.

Page 36

et al.: Alloantigen-reactive Th1 development in IL-12-deficient mice. J Immunol 1998;160: 1132–1138. de Jong R, Altare F, Haagen IA, Elferink DG, van Boer T, Vriesman PJ, et al.: Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998;280: 1435–1438. Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, et al.: Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 1998;280:1432–1435. Trinchieri G, Scott P: Interleukin12: a proinflammatory cytokine with immunoregulatory functions. Res Immunol 1995;146(7–8): 423–431. Chua AO, Chizzonite R, Desai BB, Truitt TP, Nunes P, Minetti LJ, et al: Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol 1994;153(1): 128–136. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, et al.: A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci USA 1996;93(24):14,002–14,007. Szabo SJ, Dighe AS, Gubler U, Murphy KM: Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 1997;185(5):817–824. Naeger LK, McKinney J, Salvekar A, Hoey T: Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling. J Biol Chem 1999; 274(4):1875–1878. Jacobson NG, Szabo SJ, WeberNordt RM, Zhong Z, Schreiber RD, Darnell JE Jr, et al.: Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4 J Exp Med 1996; 181(5):1755-1762. Kaplan MH, Sun YL, Hoey T, Grusby MJ: Impaired IL-12

69.

70.

71.

72.

73.

74.

75.

76.

77.

responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 1999;382(6587): 174–177. Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, et al.: The Ets transcription factor ERM is Th1specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci USA 1999;96(7):3888–3893. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH:A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100(6): 655–669. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH: Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 2002;295(5553):338–342. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, et al.: Role of T-bet in commitment of TH1 cells before IL-12dependent selection. Science 2001; 292(5523):1907–1910. Rodriguez-Palmero M, Hara T, Thumbs A, Hunig T: Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T helper type 2 differentiation in vitro and in vivo. Eur J Immunol 1999;29(12):3914–3924. Chen CH, Zhang DH, LaPorte JM, Ray A: Cyclic AMP activates p38 mitogen-activated protein kinase in Th2 cells: phosphorylation of GATA-3 and stimulation of Th2 cytokine gene expression. J Immunol 2000;165(10): 5597–5605. Gorelik L, Fields PE, Flavell RA: Cutting edge:TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression J Immunol 2000;165(9):4773–4777. Heath VL, Murphy EE, Crain C, Tomlinson MG, O’Garra A: TGFbeta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 2000;30(9):2639–2649. Blokzijl A, ten Dijke P, Ibanez CF: Physical and functional interaction

Zhou and Ouyang

IR28/1,03,25-38,14pgs

78.

79.

80.

81.

82.

83.

84.

7/25/03 9:39 AM

between GATA-3 and Smad3 allows TGF-beta regulation of GATA target genes. Curr Biol 2002;12(1):35–45. Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O’Garra A, et al.: GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med 2000;192(1):105–115. Zhou M, Ouyang W, Gong Q, Katz SG, White JM, Orkin SH, et al.: Friend of GATA-1 represses GATA-3-dependent activity in CD4+ T cells. J Exp Med 2001; 194(10):1461–1471. Ranganath S, Murphy KM: Structure and specificity of GATA proteins in Th2 development. Mol Cell Biol 2001;21(8):2716–2725. Dasen JS, O’Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, et al.: Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell 1999;97:587–598. Tsai SF, Strauss E, Orkin SH: Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA1 as a positive regulator of its own promoter Genes Dev 1991;5(6): 919–931. Das J, Chen CH, Yang L, Cohn L, Ray P, Ray A: A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol 2001;2(1):45–50. Tsang AP,Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, et al.:

Role of GATA-3 in Th1 and Th2 Differentiation

Page 37

85.

86.

87.

88.

89.

90.

FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation Cell 1997;90(1): 109–119. Tsang AP, Fujiwara Y, Hom DB, Orkin SH: Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev 1998;12(8):1176–1188. Cubadda Y, Heitzler P, Ray RP, Bourouis M, Ramain P, Gelbart W, et al.: U-Shaped encodes a zinc finger protein that regulates the proneural genes achaete and scute during the formation of bristles in Drosophila. Genes Dev 1997; 11(22):3083–3095. Tevosian SG, Deconinck AE, Cantor AB, Rieff HI, Fujiwara Y, Corfas G, et al.: FOG-2: a novel GATA-family cofactor related to multitype zinc-finger proteins friend of GATA-1 and U-shaped. Proc Natl Acad Sci USA 1999; 96(3):950–955. Svensson EC, Tufts RL, Polk CE, Leiden JM: Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes. Proc Natl Acad Sci USA 1999;96(3):956–961. Miaw SC, Choi A,Yu E, Kishikawa H, Ho IC: ROG, repressor of GATA, regulates the expression of cytokine genes. Immunity 2000; 12(3):323–333. Dent AL, Shaffer AL,Yu X,Allman D, Staudt LM: Control of inflammation, cytokine expression, and germinal center formation by

91.

92.

93.

94.

95.

96.

BCL. Science 1997;276(5312): 589–592. Dent AL, Hu-Li J, Paul WE, Staudt LM: T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc Natl Acad Sci USA 1998;95(23):13,823–13,828. Toney LM, Cattoretti G, Graf JA, Merghoub T, Pandolfi PP, DallaFavera R, et al.: BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 2000; 1(3):214–220. Gourley T, Roys S, Lukacs NW, Kunkel SL, Flavell RA, Chang CH: A novel role for the major histocompatibility complex class II transactivator CIITA in the repression of IL-4 production. Immunity 1999;10(3):377–386. Nakamura Y, Ghaffar O, Olivenstein R, Taha RA, Soussi-Gounni A, Zhang DH, et al.: Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol 1999; 103(2):215–222. Finotto S, De Sanctis GT, Lehr HA, Herz U, Buerke M, Schipp M, et al.: Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J Exp Med 2001;193(11): 1247–1260. Zhang DH,Yang L, Cohn L, Parkyn L, Homer R, Ray P, et al.: Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity 1999;11(4): 473–482.

37