Interleukin-4 and Interleukin-13 Signaling Connections Maps

Kelly-Welch, Ann E.; Hanson, Erica M.; Boothby, Mark; Keegan, Achsah

doi:10.1126/science.1085458

Cited by 371 publications

(306 citation statements)

References 19 publications

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“…The MyD88-independent signaling pathways preferentially eliciting development of Th2-biased responses are not well characterized. Our results clearly implicate p110d as a major signaling axis in Th2 induction.Signaling through the IL-4 receptor is known to activate PI3K signaling [30,31], and we have recently shown a requirement for p110d in IL-4 signaling in B cells [18]. The phenotype we describe here is similar to that seen in STAT6-deficient mice, which are defective in IL-4 signaling [32,33].…”

supporting

confidence: 71%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

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supporting

confidence: 71%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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“…Activation of both IL-13 and IL-4 membrane-bound heterodimeric receptors induces receptor molecule dimerization and activation of the Janus family members of inner membrane-bound tyrosine kinases, which then phosphorylate and initiate the nuclear transport of STAT-6 transcription factors [9]. However, studies in murine models of asthma have indicated that IL-13 rather than IL-4 appears to be critical for the development of allergic airway inflammation, hyperresponsiveness and matrix remodeling in asthma [30][31][32][33][34][35]. In the present study, we observed that overexpression of c-Maf, in the absence of a coincident overexpression of GATA-3, but in the presence of IL-2, down-regulates IL-13 but not IL-4 production in developing and polarized lung CD4 + T cells (Fig.…”

Section: Discussionmentioning

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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“…5). Several studies have demonstrated that IL-13 also activates both PI3K and STAT6 pathway in various kinds of cells (37)(38)(39)(40). Furthermore, they were reported to be involved in type I collagen expression in some situations (41)(42)(43).…”

Section: Il-13 Induces Type I Collagen Genementioning

confidence: 99%

Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts

Jinnin¹,

Ihn²,

Yamane

et al. 2004

Journal of Biological Chemistry

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Interleukin (IL)-13 is a novel lymphokine produced by activated Type 2 helper cells. In this study, we examined the target genes of IL-13 by the cDNA microarray analysis in human dermal fibroblasts. We focused on the human ␣2(I) collagen gene, which was one of the IL-13-induced genes by the microarray analysis. IL-13 induced type I collagen protein as well as mRNA in a dose-dependent manner. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the IL-13-mediated up-regulation of ␣2(I) collagen mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up-regulation. In addition, IL-13 treatment induced the promoter activity of ␣2(I) collagen by nuclear run-on transcription assay and chloramphenicol acetyltransferase assay. IL-13-mediated transcriptional activation of ␣2(I) collagen gene or type I collagen protein up-regulation was inhibited by the treatment of fibroblasts with a selective phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or STAT6 antisense oligonucleotide, but not by PD98059, a specific inhibitor of MEK/ERK, or SB202190 or SB203580, specific inhibitors of p38 MAPK; IL-13 induced the phosphorylation of PI3K p85 regulatory subunit and STAT6. These results suggest that IL-13 may play a role in the regulation of extracellular matrix and indicate the possible therapeutic value of the blockade of IL-13 signaling pathways via PI3K and STAT6 in fibrosis.

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Interleukin-4 and Interleukin-13 Signaling Connections Maps

Cited by 371 publications

References 19 publications

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

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

Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts

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