Untangling the Complex Web of IL-4-and IL-13-Mediated Signaling Pathways

Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Science Signaling (Impact Factor: 6.28). 02/2008; 1(51):pe55. DOI: 10.1126/scisignal.1.51.pe55
Source: PubMed


Unraveling the exact signaling events mediating the distinct functions of the T cell-derived cytokines interleukin-4 (IL-4) and IL-13 has been challenging because they are structurally similar and share a functional signaling receptor chain. A study now proposes a potential molecular mechanism to explain the functional differences between IL-4 and IL-13 that involves the ability of IL-4, but not IL-13, to effectively activate the insulin receptor substrate-2 (IRS-2) signaling cascade through binding to its receptor. A better understanding of the interactions of IL-4 and IL-13 with their cognate receptors may facilitate the development of therapies without unintended side effects.

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    • "TRAM-34 did not inhibit migration of control (unstimulated) microglia, but fully inhibited the increased migratory capacity of IL-4-treated cells (Figure 7A). IL-4 can act as a mitogen (reviewed in Wills-Karp and Finkelman, 2008), so it is important that the total cell density was not affected by IL-4 (or TRAM-34) over the 24 h test period (Figure 7B). As for the increase in KCa3.1 current (Figure 3E), protein synthesis was necessary for the enhanced migration; cycloheximide abolished the increase in IL-4-treated cells but had no effect on unstimulated microglia (Figure 7C). "
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    ABSTRACT: The Ca2+-activated K+ channel, KCa3.1 (KCNN4/IK1/SK4), contributes to ‘classical’, pro-inflammatory activation of microglia, and KCa3.1 blockers have improved the outcome in several rodent models of CNS damage. For instance, blocking KCa3.1 with TRAM-34 rescued retinal ganglion neurons after optic nerve damage in vivo and, reduced p38 MAP kinase activation, production of reactive oxygen and nitrogen species, and neurotoxicity by microglia in vitro. In pursuing the therapeutic potential of KCa3.1 blockers, it is crucial to assess KCa3.1 contributions to other microglial functions and activation states, especially the IL-4-induced ‘alternative’ activation state that can counteract pro-inflammatory states. We recently found that IL-4 increases microglia migration—a crucial function in the healthy and damaged CNS—and that KCa3.1 contributes to P2Y2 receptor-stimulated migration. Here, we discovered that KCa3.1 is greatly increased in alternative-activated rat microglia and then contributes to an enhanced migratory capacity. IL-4 up-regulated KCNN4 mRNA (by 6 hr) and greatly increased the KCa3.1 current by 1 day, and this required de novo protein synthesis. The increase in current was sustained for at least 6 days. IL-4 increased microglial migration and this was reversed by blocking KCa3.1 with TRAM-34. A panel of inhibitors of signal-transduction mediators was used to analyze contributions of IL-4-related signaling pathways. Induction of KCNN4 mRNA and KCa3.1 current was mediated specifically through IL-4 binding to the type I receptor and, surprisingly, it required JAK3, Ras/MEK/ERK signaling and the transcription factor, AP-1, rather than JAK2, STAT6 or PI3K. The same receptor subtype and pathway were required for the enhanced KCa3.1-dependent migration. In providing the first direct signaling link between an IL-4 receptor, expression and roles of an ion channel, this study also highlights the potential importance of KCa3.1 in alternative-activated microglia.
    Frontiers in Cellular Neuroscience 07/2014; 8(2):183. DOI:10.3389/fncel.2014.00183 · 4.29 Impact Factor
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    • "Preferential production of the LIP form of C/EBPβ during ER stress in cultured cells was found to result in transcriptional repression of a number of inflammatory genes, including IL4RA, which is an essential component of the IL-4 and IL-13 receptors (Arensdorf and Rutkowski, 2013). Most cell types express either the IL-4 or IL-13 receptor, and signaling through IL4RA stimulates pro-inflammatory processes as diverse as B cell proliferation, IgE class-switching, TH2 cell differentiation, smooth muscle contraction, mucus hypersecretion, eosinophil requirement, fibrotic deposition, and chemokine expression (Hershey, 2003; Wynn, 2003; Wills-Karp and Finkelman, 2008; Holgate, 2011). Remarkably, while ER stress suppressed IL-4/IL-13-dependent downstream signaling, this suppression was lost in Cebpb−/− cells, indicating that the translational regulation of C/EBPβ can influence responsiveness to inflammatory signals. "
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    ABSTRACT: The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes.
    Frontiers in Genetics 12/2013; 4:256. DOI:10.3389/fgene.2013.00256
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    • "IL-4 is critical for TH2 cell differentiation and IgE synthesis, while IL-13 is predominantly responsible for inducing airway hyperesponsiveness and mucus secretion. The reason for this separation of duties is not well understood; relative abundance and differential usage of receptor complexes and signaling pathways in different cell types, together with greater quantities of IL-13 (than IL-4) produced during TH2 responses have been proposed to explain these observations (reviewed in [8]). A recent publication also suggested that there may be distinct cellular expression and localization of IL-4 and IL-13 [9]. "
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    ABSTRACT: The TH2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates TH2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling TH2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γc) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4(+) OT-II T cells were adoptively transferred into RAG2(-/-) and γc (-/-) mice and allergic lung disease was induced. Both γc (-/-) and γcxRAG2(-/-) mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2(-/-) mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γc (-/-) mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher TH2 cytokine levels in the BAL and an altered DC phenotype in the γc (-/-) recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γc-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of TH2 effectors. However, the Type I R regulates AAM protein expression in macrophages.
    PLoS ONE 08/2013; 8(8):e71344. DOI:10.1371/journal.pone.0071344 · 3.23 Impact Factor
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