1α,25‐dihydroxyvitamin D₃ inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

Abstract

Summary 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, 1α,25‐dihydroxyvitamin D3 [1α,25(OH)2D3], 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 1α,25(OH)2D3 on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis‐infected human leucocytes; we also investigated the effect of 1α,25(OH)2D3 on the secretion of interleukin‐10 (IL‐10) and prostaglandin E2 (PGE2), 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). 1α,25(OH)2D3 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 1α,25(OH)2D3 irrespective of infection. In contrast, the effects of 1α,25(OH)2D3 on the expression of TIMP‐1, TIMP‐2 and TIMP‐3 and secretion of TIMP‐1 and TIMP‐2 were small and variable. 1α,25(OH)2D3 also induced secretion of IL‐10 and PGE2 from M. tuberculosis‐infected PBMC. These findings represent a novel immunomodulatory role for 1α,25(OH)2D3 in M. tuberculosis infection.

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

“…Vitamin D also suppressed circulating concentrations of IFN-γ and IFN-γ-inducible chemokines CXCL9 and CXCL10, MMP-9, and antigen-stimulated Th1 responses. These in vivo findings are consistent with reported immunomodulatory actions of calcitriol in vitro (8,36,37). In contrast to these suppressive actions, vitamin D also attenuated treatment-induced falls in antigen-stimulated CCL5, IL-4, and IFN-α.…”

Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis

“…Experiments using selective agonists and antagonists of these two receptors indicate that ligation of nuclear VDR is both necessary and sufficient for induction of antimycobacterial responses by 1,25(OH) 2 D in vitro (12) . 1,25(OH) 2 D modulates the host response to mycobacterial infection by pleiotropic mechanisms including the induction of reactive nitrogen and oxygen intermediates (13,14) , down-regulation of the gene encoding tryptophan-aspartate containing coat protein (15) , promotion of phagolysosome fusion (16) , suppression of matrix metalloproteinase enzymes implicated in the pathogenesis of pulmonary cavitation (17) and induction of antimicrobial peptides including cathelicidin LL-37 (7,12) and human b-defensin 2 (18) . Cathelicidin LL-37 possesses antimycobacterial activity (7,19) and also induces autophagy (20,21) ; 1,25(OH) 2 D 3 -induced antimycobacterial activity has been reported to be dependent on expression of the gene encoding cathelicidin LL-37 (22) .…”

Matrix metalloproteinase-10 and microvascular complications of type 1 diabetes: might vitamin D status be relevant?

“…Increased circulating MMP-9, inversely correlated with severity of vitamin D insufficiency, was reduced by ∼70% in response to modest improvement in vitamin D repletion in healthy South Asians [4], and circulating MMP-9 increased with reduction in vitamin D status in submariners after an 85 day submerged patrol [5]. Furthermore, MMP-10 formation, increased in peripheral blood mononuclear cells by exposure to Mycobacterium tuberculosis, was inhibited by activated vitamin D [6]. It would, therefore, be useful if Toni and colleagues could examine serum 25-hydroxyvitamin D concentrations in the participants in this study as a potential independent predictor for MMP-10 and microvascular complications, since lower vitamin D status has been found to be associated with increases in the prevalence of both diabetic retinopathy and diabetic nephropathy in a study of patients with type 2 diabetes [7].…”