IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med

Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC 5W3864, 10 Center Drive, Bethesda, Maryland 20892, USA.
Nature Medicine (Impact Factor: 28.05). 02/2006; 12(1):99-106. DOI: 10.1038/nm1332
Source: PubMed

ABSTRACT Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.

Download full-text


Available from: Raj Puri, Aug 23, 2015
  • Source
    • "Engagement of IL-4/IL-13 to the receptors triggers cell signalling via JAK/STAT6 dependent mechanisms [25]. A second receptor, IL-13R␣2, binds IL-13 with high affinity and is thought to be a decoy receptor sequestering IL-13 [24], although some studies suggest an uncharacterised signalling activity [26]. Previously, Ahlers et al. [27] demonstrated that soluble IL-13R␣2- Fc decoy receptor together with GM-CSF and CD40L as molecular adjuvants can enhance magnitude HIV Env-specific CD8+ CTL peptide vaccine response. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B cell immunity are required for protection.
    Vaccine 08/2014; 32(43). DOI:10.1016/j.vaccine.2014.08.023 · 3.49 Impact Factor
    • "The Type 2 receptor is a heterodimer consisting of the IL-4Ra subunit and the IL-13Ra1 subunit. IL-13, but not IL-4, can also bind to IL-13Ra2 that was believed to function as a decoy receptor controlling IL-13 signaling (Chiaramonte et al., 2003; Zheng et al., 2003), but has also been found to have signaling capabilities (Fichtner-Feigl et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro- and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.
    Immunological Investigations 10/2013; 42(7):555-622. DOI:10.3109/08820139.2013.822766 · 1.90 Impact Factor
  • Source
    • "Given that both TGF-β1 and IL-13 are critical for organ fibrosis, synergic signaling crosstalk during fibrogenesis between these two major pro-fibrotic cytokines is always a hot topic. IL-13 cooperates with TGF-β1 to induce fibrosis in some settings (Lee et al., 2001; Lanone et al., 2002; Fichtner-Feigl et al., 2006). For example, IL-13 is known as a potent inducer of matrix metalloproteinases-9 and cathepsin-based proteolytic pathways which stimulate cleavage of latency-associated peptide thus activate TGF-β (Lee et al., 2001; Lanone et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Liver fibrosis is the final common pathway of chronic liver diseases irrespective of etiology. However, etiology deeply impacts progression and characteristics of liver fibrogenesis. IL-13 is the dominant pro-fibrotic cytokine in Schistosomiasis associated liver fibrogenesis. In vitro, IL-13 directly induces expression of fibrosis-associated genes, e.g., collagens or connective tissue growth factor, in hepatic stellate cells. Recently, potential effects of IL-13 in non-Schistosomiasis associated liver fibrosis have been uncovered. This review summarizes the potential roles of IL-13 in chronic liver disease of different etiologies, and the downstream events mediating IL-13 signaling in liver fibrogenesis.
    Frontiers in Immunology 05/2012; 3:116. DOI:10.3389/fimmu.2012.00116
Show more