Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WEThe IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17: 701-738

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/1999; 17(1):701-38. DOI: 10.1146/annurev.immunol.17.1.701
Source: PubMed


Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4R alpha chain and the common gamma chain (gamma c), resulting in a series of phosphorylation events mediated by receptor-associated kinases. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

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    • "Also IL-4 modulates the production of Th2 associated cytokines such as IL-5, IL-10, and IL-13. The human IL-4 is also involved in the suppression of protective Th1 response and act as an inhibitor of IFN-V producing CD4 + T cells [18] [19] and stimulates the production of IgG4 [20]. IL-4 along with IL-13 were reported to associate with parasite survival and persistence of infection [21] [22]. "
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    ABSTRACT: Visceral Leishmaniasis (VL) is the most severest form of Leishmaniasis and resistance to infection is mediated by cellular immune responses. Interleukin 4 (IL-4) orchestrates of Th2 and Th1 immune responses during infections. In this study, we aimed to investigate possible association between three functional IL-4 polymorphisms −590C/T (rs2243250), −34C/T (rs2070874) and 70bp VNTR (rs79071878 in intron3) with VL in an Indian cohort comprising of 197 VL patients and 193 healthy controls. The three investigated IL-4 polymorphisms were in strong linkage disequilibrium. The investigated IL-4 alleles, genotypes and the reconstructed haplotypes were not significantly distributed between the VL patients and healthy controls. Our study signifies no possible association of functional IL-4 polymorphisms with Indian VL and postulate other vital genes involved in the IL-4 pathway may provide genetic clues to elucidate of IL-4 regulation and immune-pathogenesis during VL.
    Full-text · Article · Oct 2014 · Human Immunology
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    • "Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a negative regulator of the Th2 related IL-4Rα signaling pathway. Once recruited, phosphorylated, and activated, SHP-1 binds to and dephosphorylates its target molecules and terminates the activation signaling [9]. When SHP-1 enzyme activity is absent or reduced, cytokine/growth factor signaling goes unchecked, which may lead to abnormal responses. "
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    ABSTRACT: Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev) mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs) were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13), chemokines (eotaxin), and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "IL-4 signals through STAT6 molecule, activates expression of Th2 associated transcription factors such as GATA3 and c-Maf, and induces expression of Th2 signature cytokines, IL-4, IL-5, and IL-13 [28]. IL-4 exerts its biologic function using two distinct types of IL-4 receptors, type I (IL-4Rα and γc) and type II (IL-4Rα and IL-13Rα1) receptors [29]. The expression of both receptors is different depending on the cell types. "
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    ABSTRACT: The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.
    Full-text · Article · Jul 2014 · Research Journal of Immunology
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