Role of Interleukin 36[gamma] in Host Defense Against Tuberculosis

Tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. The roles of the interleukin 1 (IL-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. In contrast, the regulation of interleukin 36[gamma] (IL-36[gamma]), a recently described member of the IL-1 family, and its immunological relevance in host defense remain largely unknown. Here we show that Mycobacterium tuberculosis infection of macrophages induces IL-36[gamma] production in a 2-stage-regulated fashion. In the first stage, microbial ligands trigger host Toll-like receptor and MyD88-dependent pathways, leading to IL-36[gamma] secretion. In the second stage, endogenous IL-1[beta] and interleukin 18 further amplify IL-36[gamma] synthesis. The relevance of this cytokine in the control of M. tuberculosis is demonstrated by IL-36[gamma]-induced antimicrobial peptides and IL-36 receptor-dependent restriction of M. tuberculosis growth. Thus, we provide first insight into the induction and regulation of the proinflammatory cytokine IL-36[gamma] during tuberculosis.