Regulated Expression of the IL-31 Receptor in Bronchial and Alveolar Epithelial Cells, Pulmonary Fibroblasts, and Pulmonary Macrophages

Abstract

Interleukin-31 (IL-31), an IL-6 cytokine family member, is proposed to play a role in animal models of airway hyperreactivity. It is produced by activated T cells and signals via a heterodimeric receptor complex composed of IL-31Ralpha and OSMRbeta. Only low levels of IL-31Ralpha expression have been demonstrated in pulmonary epithelial cell lines, however, and little is known about the ability to regulate its expression and signaling. Therefore, primary cultures of human bronchial and alveolar epithelial cells, pulmonary fibroblasts, pulmonary macrophages, and established lines of immortalized bronchial epithelial cells (HBE) and alveolar carcinoma cells (A549) were analyzed by RT-PCR, immunoblotting, and thymidine incorporation. Distinct, cell type-specific regulation of IL-31Ralpha expression was detected. Transforming growth factor-beta (TGF-beta) enhanced IL-31Ralpha mRNA expression in primary cultures and established lines of epithelial cells, but not in macrophages. In contrast, interferon-gamma (IFN-gamma) induced IL-31Ralpha mRNA expression in macrophages. IL-31Ralpha protein expression was below detection threshold in primary epithelial cell cultures but was detectable in A549 cells and increased with TGF-beta treatment. In HBE and A549 cells, TGF-beta pretreatment increased IL-31-mediated Stat3 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. In A549 cells, TGF-beta magnified IL-31-dependent suppression of proliferation. The data suggest that increased IL-31Ralpha expression correlates with an enhanced response to IL-31.

Il-31 Does not Correlate to Pruritus Related to Early Stage Cutaneous T-cell Lymphomas but is Involved in Pathogenesis of the Disease

“…It is likely that additional signals from different cells modulate IL-31 activity in cell proliferation (22). Although recent studies have demonstrated that IL-31 is effective in suppressing the proliferation of lung epithelial cells (48,49). Furthermore it is known that IL-31 stimulates STAT-3 and STAT-5 (18,22), by which some cytokines are involved in haematopoiesis (50).…”

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

“…IFNg stimulation results in a STAT1-dependent increase in IL-31RA transcription in monocytes, macrophages, dendritic cells, keratinocytes and dermal microvascular endothelial cells [39,131,[135][136][137][138]. Promoter analysis and chromatin IP assays demonstrated STAT1 binding to the IL-31RA promoter [138].…”

“…Absence of the type II IL-4 receptor attenuated the expression of IL-31RA in vivo during allergic asthma [139]. In primary cultures and established lines of epithelial cells IL-31RA mRNA was induced by TGFb [135]. A particular high expression of IL-31RA and OSMRb was found in small diameter dorsal root ganglia (DRG) neurons and repeated administration of IL-31 resulted in up-regulation of both receptors in DRG and intensified long-lasting scratching behavior in treated mice [140,141].…”

Analytic Review: Interleukin-6 in Surgery, Trauma, and Critical Care: Part I: Basic Science

“…Interleukin-31Rα, although often classified as a β subunit, can only transduce signal when combined with another β subunit. 52 The β subunits may combine with another β subunit or with the α subunits of selected IL-6 cytokines to form dimeric or multi-meric complexes. 70,81 The shared subunit for the IL-6 cytokines, with the exception of IL-31, is gp130.…”

“…Interleukin-31 signals via IL-31Rα/OSMRβ. 52 Finally, CNTF and CLC signal via the CNTFRa/LIFR/gp130 complex. 70 …”