title: 1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection.
abstract: Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], has previously been reported to inhibit secretion of MMP-9 in human monocytes (MN), but its influence on the secretion and gene expression of MMP and tissue inhibitors of MMP (TIMP) in M. tuberculosis-infected cells has not previously been investigated. We therefore determined the effects of 1alpha,25(OH)(2)D(3) on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis-infected human leucocytes; we also investigated the effect of 1alpha,25(OH)(2)D(3) on the secretion of interleukin-10 (IL-10) and prostaglandin E(2) (PGE(2)), both transcriptional regulators of MMP expression. We found that M. tuberculosis induced expression of MMP-1, MMP-7 and MMP-10 in MN and MMP-1 and MMP-10 in peripheral blood mononuclear cells (PBMC). 1alpha,25(OH)(2)D(3) significantly attenuated M. tuberculosis-induced increases in expression of MMP-7 and MMP-10, and suppressed secretion of MMP-7 by M. tuberculosis-infected PBMC. MMP-9 gene expression, secretion and activity were significantly inhibited by 1alpha,25(OH)(2)D(3) irrespective of infection. In contrast, the effects of 1alpha,25(OH)(2)D(3) on the expression of TIMP-1, TIMP-2 and TIMP-3 and secretion of TIMP-1 and TIMP-2 were small and variable. 1alpha,25(OH)(2)D(3) also induced secretion of IL-10 and PGE(2) from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1alpha,25(OH)(2)D(3) in M. tuberculosis infection.
authors.affiliation: Division of Mycobacterial Research, National Institute for Medical Research, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Coussens
authors.forename: Peter M
authors.initials: PM
authors.lastname: Timms
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Boucher
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Venton
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Ashcroft
authors.forename: Keira H
authors.initials: KH
authors.lastname: Skolimowska
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Newton
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Robert N
authors.initials: RN
authors.lastname: Davidson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Griffiths
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Martineau
mesh_terms: D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000382:microbiology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D014376:Tuberculosis / Q000097:blood / Q000201:enzymology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; C118756:dihydroxy-vitamin D3; D016753:Interleukin-10; D014807:Vitamin D; D020782:Matrix Metalloproteinases; D015232:Dinoprostone