Journal
PATHOGENS AND DISEASE
Volume 70, Issue 1, Pages 51-60Publisher
OXFORD UNIV PRESS
DOI: 10.1111/2049-632X.12075
Keywords
Mycobacterium tuberculosis; RD1; macrophage; IL-1 alpha; calpain; calcium
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Funding
- Ministry of Education, Science, Culture and Sports of Japan
- Japan Society for the Promotion of Science
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [24590522] Funding Source: KAKEN
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Region of difference 1 (RD1) is a genomic locus in the Mycobacterium tuberculosis genome that has been shown to participate in the virulence of the bacterium, induction of cell death, and cytokine secretion in infected macrophages. In this study, we investigated the role of RD1 in interleukin-1 (IL-1) secretion. M.tuberculosis H37Rv strain, but not a mutant strain deficient for RD1 (RD1), significantly induced IL-1 secretion from infected macrophages. Although IL-1 secretion was only observed in H37Rv-infected macrophages, there was no difference in the level of IL-1 transcription and pro-IL1 synthesis after infection with H37Rv and RD1. Interestingly, RD1 infection did not increase intracellular Ca2+ levels, and Ca2+ chelators markedly inhibited IL-1 secretion in response to H37Rv infection. Moreover, the inability of RD1 to induce IL-1 secretion was restored by treatment with the calcium ionophore A23187. A significant increase in calpain activity was detected in macrophages infected with H37Rv, but not with RD1, and calpain inhibitors abrogated IL-1 secretion. Taken together, these results suggest that in M.tuberculosis-infected macrophages, RD1 contributed to maturation and secretion of IL-1 by enhancing the influx of Ca2+ followed by calpain activation.
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