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Immunology - Physiology - Respiratory Medicine

IL-36a Exerts Pro-Inflammatory Effects in the Lungs of Mice
Published: Thursday, September 20, 2012
Author: Ravisankar A. Ramadas et al.

by Ravisankar A. Ramadas, Susan L. Ewart, Yoichiro Iwakura, Benjamin D. Medoff, Ann Marie LeVine

Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5– IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36a (IL-1F6) and test the hypothesis that IL-36a acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36a induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1aß-/- mice in vivo. IL-36a induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1aß-/- mice in vivo. In addition, intratracheal instillation of IL-36a enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1aß-/- mice in vivo. Furthermore, in vitro incubation of CD11c+ cells with IL-36a resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFa. IL-36a increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c+ cells to induce CD4+ T cell proliferation in vitro. Furthermore, stimulation with IL-36a activated NF-?B in a mouse macrophage cell line. These results demonstrate that IL-36a acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1a and IL-1ß. The current study describes the pro-inflammatory effects of IL-36a in the lung, demonstrates the functional redundancy of IL-36a with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases.