title: IL-36α exerts pro-inflammatory effects in the lungs of mice.
abstract: 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-36α (IL-1F6) and test the hypothesis that IL-36α acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36α induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1αβ(-/-) mice in vivo. IL-36α 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-1αβ(-/-) mice in vivo. In addition, intratracheal instillation of IL-36α enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1αβ(-/-) mice in vivo. Furthermore, in vitro incubation of CD11c(+) cells with IL-36α resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFα. IL-36α 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-36α activated NF-κB in a mouse macrophage cell line. These results demonstrate that IL-36α acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1α and IL-1β. The current study describes the pro-inflammatory effects of IL-36α in the lung, demonstrates the functional redundancy of IL-36α 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.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. rramadas@partners.org
authors.forename: Ravisankar A
authors.initials: RA
authors.lastname: Ramadas
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ewart
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: LeVine
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D018845:CD11 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016328:NF-kappa B; C543716:interleukin 1F6, mouse