Role of IL-32 in the Vitamin D Response Pathway against Mycobacterium tuberculosis

Understanding the innate immune response required in host defense against bacterial infections is crucial to treating Mycobacterium tuberculosis. The innate immune response against mycobacteria responds via the vitamin D-mediated antimicrobial program in macrophages. This vitamin D response (VDR) pathway requires the release of the immunodolutary cytokines, interleukin 15 (IL -15) or interferon gamma (IFN-γ) or can be triggered upon bacterial recognition from toll-like receptors (TLR). The pathway requires the conversion of inactive vitamin D (hydroxyvitamin 25D3) to the active vitamin D (prohormone 1,25D) by the enzyme CYP27B1. Thereafter, the VDR pathway upregulates antimicrobial peptides, cathelicidin (CATH) and defensin 4 gene (DEFB4), which directly kill mycobacteria. Our preliminary microarray studies demonstrate that IL-15 upregualtes interleukin 32 (IL-32), a pro-inflammatory cytokine that also plays a role in host defense against M. tuberculosis. IL-32 is sufficient to induce the VDR pathway and that IFNG and IL-15 induction of the VDR pathway is dependent on IL-32. Human peripheral blood monocytes treated with IL-32 demonstrated induction of CYP27B1, CATH, and DEFB4 by quantitative polymerase chain reaction. In the siIL-32 knockdown, monocytes treated with IFN-γ or IL-15 demonstrated lower levels of induction of CYP27B1 mRNA. In the control siRNA, the levels of induction of CYP27B1 remained the same suggesting induction of the VDR pathway by IFN-γ and IL-15 does depend on IL-32.  A better comprehension of IL-32’s role in the VDR pathway serves to provide therapeutic approaches in a non-abiotic manner to successfully overcome multi-drug resistant strains in M. tuberculosis.