A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production.

IL-17A is produced from Th17 cells, and is involved in many autoimmune and inflammatory diseases. IL-13R has not previously been reported to be functionally expressed on T cells; however, we found that purified BALB/c CD4(+) cells polarized to Th17 with TGF-beta, IL-6, and IL-23 have increased mRNA and protein expression of IL-13R alpha1 and mRNA expression of IL-4R alpha compared with Th0, Th1, or Th2 polarized cells. The addition of IL-13 at Th17 polarization negatively regulated IL-17A and IL-21 expression, and reduced the number of CD4(+) T cells producing IL-17A. Further, adding IL-13 at the time of Th17 cell restimulation attenuated IL-17A expression. CD4(+) Th17 polarized cells from IL-4 knockout (KO) mice also had IL-13-induced inhibition of IL-17A production, but this was not observed in IL-4R KO and STAT6 KO mice. Addition of IL-13 at polarization increased IL-13R expression in wild-type Th17 cells. Further, IL-13 administration during Th17 polarization down-regulated retinoic acid-related-gammaT, the transcription required for Th17 development; increased STAT6 phosphorylation, and up-regulated GATA3, the transcription factor activated during the development of Th2 cells. This IL-13-mediated effect was specific to Th17 cells as IL-13 neither decreased IFN-gamma expression by Th1 cells nor affected Th2 cell production of IL-4. Collectively, we have shown that Th17 cells express a functional IL-13R and that IL-13 negatively regulates IL-17A and IL-21 production by decreasing retinoic acid-related-gammaT expression and while increasing phosphorylation of STAT6 and GATA3 expression. Therefore, therapeutic intervention inhibiting IL-13 production could have adverse consequences by up-regulating Th17 inflammation in certain disease states.

Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension.

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed. OBJECTIVES: The objective of this study was to assess the possible contribution of the IL-13 system to IPAH. METHODS: Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC. MEASUREMENTS AND MAIN RESULTS: Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects. CONCLUSIONS: The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.

Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model.

Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver fibrosis, progresses to cirrhosis in up to 20% of patients. We report that hepatic stellate cells (HSC) in sinusoidal lesions of liver of patients with NASH express high levels of high-affinity IL-13R (IL-13Ralpha2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13Ralpha2. HSCs engineered to overexpress IL-13Ralpha2 respond to IL-13 and induce TGFB1 promoter activity and TGF-beta1 production. We also developed NASH in rats by feeding a choline-deficient l-amino acid diet. These rats developed liver fibrosis as assessed by H&E staining, Masson's trichrome and Sirius red staining, and hydroxyproline assays. Treatment of these rats with IL-13R-directed cytotoxin caused a substantial decline in fibrosis and liver enzymes without organ toxicity. These studies demonstrate that functional IL-13Ralpha2 are overexpressed in activated HSCs involved in NASH and that IL-13 cytotoxin ameliorates pathological features of NASH in rat liver, indicating a novel role of this cytotoxin in potential therapy.

Interferon-gamma and donor MHC class I control alternative macrophage activation and activin expression in rejecting kidney allografts: a shift in the Th1-Th2 paradigm.

Organ allografts deficient in interferon-gamma (Ifng) or major histocompatibility complex (MHC) class I products develop accelerated necrosis when rejection develops, depending on perforin and granzymes. Thus Ifng-induced donor class I products deliver inhibitory signals to host inflammatory cells. We used microarrays to investigate whether Ifng-induced donor class I products also control inflammation patterns in mouse kidney allografts. Compared to wild-type (WT) allografts, many transcripts were increased in both Ifng-deficient allografts (Ifng-suppressed transcripts [GSTs]) and class I-deficient allografts (class I-suppressed transcripts [CISTs]), with 73% overlap between GSTs and CISTs. Some GSTs and CISTs reflected increased necrosis, including known injury-induced transcripts. However, many GSTs and CISTs were independent of perforin, granzymes and necrosis, and were associated with alternative macrophage activation (AMA) (e.g. arginase I [Arg1], macrophage elastase [Mmp12] and macrophage mannose receptor 1 [Mrc1]). AMA transcripts were induced despite absence of host interleukin (IL)4 and IL13 receptors. The AMA inducer may be activins, whose genes (inhibin A [InhbA] and inhibin B [InhbB]) were increased in all allografts with AMA. We conclude that in allograft rejection, Ifng acts via donor Ifng receptors (Ifngr) to induce donor class Ia and Ib products, which engage host inflammatory cells to limit perforin-granzyme-mediated damage and prevent AMA associated with inhibition of activin expression. Thus, Ifng may control T helper type 2 (Th2) cell inflammation by induction of class I products.

[Interleukin 13 and interleukin 13 receptor involvement in systemic sclerosis]. / Implication de l'interleukine 13 et de son récepteur dans la sclérodermie systémique.

PURPOSE: Interleukin 13 is an immunoregulatory cytokine predominantly secreted by activated Th2 cells. It has similar functions with interleukin 4 and they share a common receptor. However, unlike interleukin 4, l'interleukin 13 does not appear to be important in the initial differentiation of CD4 T into Th2-type cells, but rather appears to be necessary in the effector phase of inflammation and fibrosis. This cytokine has been involved in recent works in allergic inflammation and in some fibrotic diseases leading to a scientific interest to analysis the role of interleukin 13 in systemic sclerosis (scleroderma). MAIN POINTS: Systemic sclerosis is an autoimmune disease characterized by vascular alteration and skin and visceral fibrosis. A genetic background associated with susceptibility is supposed. Knowing the profibrogenic properties of interleukin 13, we asked if polymorphisms located in interleukin 13 and interleukin 13 receptor genes could be associated with systemic sclerosis. We observed significant associations between IL13 and IL13RA2 gene polymorphisms and the disease, particularly the cutaneous diffuse form of the disease. PERSPECTIVES AND PROJECTS: Results concerning the involvement of interleukin 13 pathway in systemic sclerosis need to be confirmed on another larger population. Functional studies will be done to explain the effect of these associations. We feel that IL13/IL13R pathway is interesting as immunomodulation with the interleukin 13 receptor inhibitor is possible in therapy.

Regulation of inflammation by interleukin-4: a review of "alternatives".

Studies of IL-4 have revealed a wealth of information on the diverse roles of this cytokine in homeostatic regulation and disease pathogenesis. Recent data suggest that instead of simple linear regulatory pathways, IL-4 drives regulation that is full of alternatives. In addition to the well-known dichotomous regulation of Th cell differentiation by IL-4, this cytokine is engaged in several other alternative pathways. Its own production involves alternative mRNA splicing, yielding at least two functional isoforms: full-length IL-4, encoded by the IL-4 gene exons 1-4, and IL-4δ2, encoded by exons 1, 3, and 4. The functional effects of these two isoforms are in some ways similar but in other ways quite distinct. When binding to the surface of target cells, IL-4 may differentially engage two different types of receptors. By acting on macrophages, a cell type critically involved in inflammation, IL-4 induces the so-called alternative macrophage activation. In this review, recent advances in understanding these three IL-4-related branch points--alternative splicing of IL-4, differential receptor engagement by IL-4, and differential regulation of macrophage activation by IL-4--are summarized in light of their contributions to inflammation.

Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13.

The Th2 cytokines interleukin (IL)-4 and -13 are acknowledged regulators of lymphocyte proliferation and activation. They have also been well studied in the regulation of various myeloid-derived populations in tumor biology. It has become clear, however, that both cytokines can have direct effects on epithelial tumor cells expressing appropriate receptors. Changes in tumor proliferation, survival, and metastatic capability have all been ascribed to IL-4 and/or IL-13 action. Here, we evaluate the evidence to support direct tumor-promoting roles of these cytokines. We also identify the questions that should be addressed before proceeding with therapeutic approaches based on neutralization of IL-4 or IL-13 pathways.