IL-13 receptor isoforms: Breaking through the complexity

Tabata, Yasuhiro; Hershey, Gurjit K. Khurana

doi:10.1007/s11882-007-0051-x

Cited by 72 publications

(67 citation statements)

References 54 publications

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“…This result is consistent with a previous gene-expression study in which the IL4Rα and IL13Rα1 chains were reported to be upregulated in kidneys of the cpk polycystic mouse model (20). We also investigated the expression of the IL13Rα2 receptor, which lacks the intracellular signaling domain and is thought to be decoy receptor and inhibitor of the STAT6 pathway (21). Strikingly, the IL13Rα2 receptor is expressed in control kidneys but is strongly down-regulated in cysts (Fig.…”

Section: Stat6supporting

confidence: 92%

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

Olsan

Mukherjee

Wulkersdorfer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood. We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/ paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.signal transduction | cytokines | preclinical

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Section: Stat6supporting

confidence: 92%

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

Olsan

Mukherjee

Wulkersdorfer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-13 also binds to the other IL-13 receptor subtype a2 (IL-13Ra2) with an even higher affinity. This receptor has been thought to be a decoy receptor due to its short cytoplasmic tail, but it has been shown that IL-13Ra2 may have some signalling capabilities, regulating IL-13 signalling pathways (Tabata and Khurana Hershey, 2007;Andrews et al, 2009). In the canonical pathway triggered by IL-4 and IL-13, binding of either IL-4 to IL-4Ra in IL-4R Type 1 or 2, or IL-13 to IL-13Ra1 in IL-13 receptors results in an activation of janus tyrosine kinase 1 (JAK1), which leads to phosphorylation of tyrosine residues of IL-4Ra, which subsequently liaisons with the transcription factor signal transducers and activators of transcription 6 (STAT6).…”

Section: Introductionmentioning

confidence: 99%

IL‐4 and IL‐13 inhibit IL‐1β and TNF‐α induced kinin B₁ and B₂ receptors through a STAT6‐dependent mechanism

Souza

Brechter

Reis

et al. 2013

British J Pharmacology

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Background and PurposeBone resorption induced by interleukin‐1β (IL‐1β) and tumour necrosis factor (TNF‐α) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation‐induced bone resorption can be impaired by IL‐4 and IL‐13. The aim was to investigate if expression of B1 and B2 kinin receptors can be affected by IL‐4 and IL‐13.Experimental ApproachWe examined effects in a human osteoblastic cell line (MG‐63), primary human gingival fibroblasts and mouse bones by IL‐4 and IL‐13 on mRNA and protein expression of the B1 and B2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6‐/‐ mice.Key ResultsIL‐4 and IL‐13 decreased the mRNA expression of B1 and B2 kinin receptors induced by either IL‐1β or TNF‐α in MG‐63 cells, intact mouse calvarial bones or primary human gingival fibroblasts. The burst of intracellular calcium induced by either bradykinin (B2 agonist) or des‐Arg10‐Lys‐bradykinin (B1 agonist) in gingival fibroblasts pretreated with IL‐1β was impaired by IL‐4. Similarly, the increased binding of B1 and B2 ligands induced by IL‐1β was decreased by IL‐4. In calvarial bones from Stat6‐deficient mice, and in fibroblasts in which STAT6 was knocked down by siRNA, the effect of IL‐4 was decreased.Conclusions and ImplicationsThese data show, for the first time, that IL‐4 and IL‐13 decrease kinin receptors in a STAT6‐dependent mechanism, which can be one important mechanism by which these cytokines exert their anti‐inflammatory effects and impair bone resorption.

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“…IL-13Ra2 is present on the cell membrane, intracellularly, and in a soluble form. Cell membrane IL-13Ra2 receptors may have some signalling capabilities, but soluble IL-13Ra2 receptors are critical endogenous modulators of IL-13 responses and may, therefore, have a more complicated function than previously thought [29]. IL-13Ra2 is upregulated in cells with heightened responses to IL-13, and increased expression levels of the receptor subunits IL-4Ra and IL-13Ra2 have been reported in fibroblasts from surgical lung biopsies of patients with idiopathic interstitial pneumonia [30,31].…”

mentioning

confidence: 99%

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma

Oh¹,

Geba²,

Molfino³

2010

Eur Respir Rev

237

164

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Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.

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IL-13 receptor isoforms: Breaking through the complexity

Cited by 72 publications

References 54 publications

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

IL‐4 and IL‐13 inhibit IL‐1β and TNF‐α induced kinin B₁ and B₂ receptors through a STAT6‐dependent mechanism

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma

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IL-13 receptor isoforms: Breaking through the complexity

Cited by 72 publications

References 54 publications

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

IL‐4 and IL‐13 inhibit IL‐1β and TNF‐α induced kinin B1 and B2 receptors through a STAT6‐dependent mechanism

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma

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IL‐4 and IL‐13 inhibit IL‐1β and TNF‐α induced kinin B₁ and B₂ receptors through a STAT6‐dependent mechanism