The Transcription Factor c-Maf Controls the Production of Interleukin-4 but Not Other Th2 Cytokines

Kim, James I.; Ho, I‐Cheng; Grusby, Michael J.; Glimcher, Laurie H.

doi:10.1016/s1074-7613(00)80073-4

Cited by 342 publications

(282 citation statements)

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“…However, IL-4 was blocked, as demonstrated by inhibition of both IL-4 mRNA and serum IgE elevations, when B7 costimulation was abrogated. These studies thus demonstrate differential regulation of IL-4 and IL-13 in T cells by costimulatory molecules during the in vivo immune response, consistent with previous studies indicating that these Th2 cytokines can be differentially regulated by certain transcription factors [10,11]. Our studies further indicate that DX5 + cells are also a major source of IL-13.…”

Section: Discussionsupporting

confidence: 91%

“…However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and GATA-3 [11] can differentially regulate these two cytokines. Consistent with these findings, several in vivo studies have recently identified IL-4-independent elevations of IL-13 associated with an IFN-c-dominant response [8,12], although the cell surface or secreted molecules that induce the development of IL-13-expressing cells in this context remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

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IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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“…Several developmentally regulated transcription factors, such as GATA-3 and c-maf, have been shown to be critical for the generation of IL-4 producing Th2 cells (Ho et al, 1996;Kim et al, 1999;Zheng and Flavell, 1997). The expression of these transcription factors is induced as Th precursor cells become Th2 e ectors.…”

Section: Stat6 and T Helper Cell Differentiationmentioning

confidence: 99%

The biology of Stat4 and Stat6

2000

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“…Furthermore, c-maf -/-mice showed greatly impaired IL-4 production, and their T cells spontaneously polarized towards a Th1 phenotype. However, under Th2-differentiating conditions, c-Maf-deficient Th2 cells produced normal amounts of Th2 cytokines, indicating that c-Maf is not required for chromatin remodeling at the IL-4/IL-13 locus but rather specifically regulates IL-4 gene expression in peripheral T lymphocytes [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…c-Maf is a transcription factor of the maf gene family expressed in Th2 but not Th1 cells [15] that is responsible for tissue-specific expression of the IL-4 gene [15][16][17]. The maf gene family includes the large maf genes (c-maf, mafB and Nrl) and the small maf genes (mafK, mafG and mafF), which lack the N-terminal half of the large maf genes containing the transactivation domain [18].…”

Section: Introductionmentioning

confidence: 99%

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

Hausding¹,

Lehr³

et al. 2004

Eur J Immunol

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The transcription factor c-Maf controls IL-4 gene expression in CD4 + T cells, and its expression is up-regulated in human asthmatic airways after allergen challenge. In the present study, we addressed the role of c-Maf in asthma by studying transgenic (Tg) mice overexpressing c-Maf in CD4 + T cells under the control of the CD2 promoter. As shown, lung CD4 + T cells of c-maf-Tg mice produced more IL-5 at the early stage (day 2) of culture in the presence of IL-4 than wild-type control cells. Consistently, c-maf-Tg mice spontaneously showed increased IL-5 expression and eosinophils in the bronchial alveolar lavage fluid (BALF) and activated IL-5 signal transduction via Raf-1 and Ras in lung eosinophils. Finally, IL-13 was suppressed in the BALF of c-maf-Tg mice and in supernatants of Tg lung CD4 + T cells cultured in the presence of IL-2. Consistently, retroviral overexpression of c-Maf suppressed IL-13 production in developing lung Th2 cells. In summary, c-Maf induces IL-5 production in lung CD4 + T cells at an early stage, but along with IL-2 suppresses IL-13 production in differentiating lung Th2 cells, thereby explaining the finding that overexpression of c-Maf does not cause airway hyperresponsiveness, a hallmark feature of asthma.

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The Transcription Factor c-Maf Controls the Production of Interleukin-4 but Not Other Th2 Cytokines

Cited by 342 publications

References 50 publications

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

The biology of Stat4 and Stat6

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

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