title: The RD1 locus in the Mycobacterium tuberculosis genome contributes to the maturation and secretion of IL-1α from infected macrophages through the elevation of cytoplasmic calcium levels and calpain activation.
abstract: 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-1α (IL-1α) secretion. M. tuberculosis H37Rv strain, but not a mutant strain deficient for RD1 (∆RD1), significantly induced IL-1α secretion from infected macrophages. Although IL-1α secretion was only observed in H37Rv-infected macrophages, there was no difference in the level of IL-1α transcription and pro-IL1α synthesis after infection with H37Rv and ∆RD1. Interestingly, ∆RD1 infection did not increase intracellular Ca(2+) levels, and Ca(2+) chelators markedly inhibited IL-1α secretion in response to H37Rv infection. Moreover, the inability of ∆RD1 to induce IL-1α 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-1α secretion. Taken together, these results suggest that in M. tuberculosis-infected macrophages, RD1 contributed to maturation and secretion of IL-1α by enhancing the influx of Ca(2+) followed by calpain activation.
authors.affiliation: Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China; Department of Microbiology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
authors.forename: Ruili
authors.initials: R
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Xi
authors.forename: Dewamitta R
authors.initials: DR
authors.lastname: Sita
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.forename: Huixin
authors.initials: H
authors.lastname: Qu
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D053582:Interleukin-1alpha / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D053582:Interleukin-1alpha; D002154:Calpain; D002118:Calcium
keywords: IL-1α; Mycobacterium tuberculosis; RD1; calcium; calpain; macrophage