IFN-γ- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37

Martineau, AR; Wilkinson, K. A.; Newton, Sandra M.; Floto, R. A.; Norman, A. W.; Skolimowska, K.; Davidson, R. N.; Sørensen, O. E.; Kampmann, B.; Griffiths, Christopher J.; Wilkinson, R.J.

doi:10.4049/jimmunol.179.12.8569-c

Cited by 49 publications

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“…32 We and others have also previously demonstrated that 1a,25(OH) 2 D 3 induces the antimicrobial peptide cathelicidin LL-37, which possesses antituberculous activity. 22,33,34 PBMC + EtOH This report describes a complementary mechanism whereby vitamin D could exert a beneficial effect on host response to M. tuberculosis by inhibiting the expression, secretion and activity of a number of MMP induced by M. tuberculosis, consequently limiting the degradation of extracellular matrix and decreasing pulmonary cavitation to preserve lung function and reduce infectiousness.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…IFN-γ is, also, critical for further expression and production of NOS2 in adaptive response (39) (Figure 1). In addition, IFN-γ secreted by T cells inside the granuloma potentiates the up-regulation of 1α-hydroxylase and inhibits the key enzyme in 1,25(OH) 2 D 3 inactivation (24-hydroxylase) (58).…”

Section: Interferon-γ γ γ γ γmentioning

confidence: 99%

“…The activation of TLRs can also up-regulate the expression of vitamin D receptor and vitamin D-1-hydroxylase genes (enzyme that metabolizes 25(OH) 2 D 3 to 1,25(OH) 2 D 3 ), leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular M. tuberculosis (8). In addition, 1,25(OH) 2 D 3 , by itself, can modulate the immune response by its nuclear receptor (VDR), where it up-regulates protective immune host defense by induction of NOS (58) and cathelicidin (9) as well as down-regulation of IFN-γ gene expression by down-regulating its promoter (59). It is known that 1,25(OH) 2 D 3 is present 1000-fold less in peripheral blood than 25(OH) 2 D 3 , and the release of these forms in the granuloma space by VDBP may modulate T cell responses.…”

Section: Interferon-γ γ γ γ γmentioning

confidence: 99%

Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

Leandro

Rocha

Cardoso

et al. 2009

Braz J Med Biol Res

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“…1,25(OH) 2 D modulates immune responses by ligating membrane VDR to induce rapid effects (within minutes) or nuclear VDR to induce genomic effects (within hours) (11) . 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) .…”

Section: Immunomodulatory Actions Of Vitamin D In Mycobacterial Infecmentioning

confidence: 99%

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

Martineau

2011

Proc. Nutr. Soc.

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Tuberculosis (TB) is a major cause of mortality, responsible for 1 . 68 million deaths worldwide in 2009. The global prevalence of latent Mycobacterium tuberculosis infection is estimated to be 32 %, and this carries a 5-20% lifetime risk of reactivation disease. The emergence of drug-resistant organisms necessitates the development of new agents to enhance the response to antimicrobial therapy for active TB. Vitamin D was used to treat TB in the pre-antibiotic era, and its active metabolite, 1,25-dihydoxyvitamin D, has long been known to enhance the immune response to mycobacteria in vitro. Vitamin D deficiency is common in patients with active TB, and several clinical trials have evaluated the role of adjunctive vitamin D supplementation in its treatment. Results of these studies are conflicting, reflecting variation between studies in baseline vitamin D status of participants, dosing regimens and outcome measures. Vitamin D deficiency is also recognised to be highly prevalent among people with latent M. tuberculosis infection in both high-and low-burden settings, and there is a wealth of observational epidemiological evidence linking vitamin D deficiency with increased risk of reactivation disease. Randomised controlled trials of vitamin D supplementation for the prevention of active TB have yet to be performed, however. The conduct of such trials is a research priority, given the safety and low cost of vitamin D supplementation, and the potentially huge public health consequences of positive results. Tuberculosis: Vitamin D: Immunomodulation: Clinical trialsTuberculosis (TB) is a major public health problem. The global prevalence of latent Mycobacterium tuberculosis (MTB) infection has been estimated at 32% (1) , and this carries a 5-20% lifetime risk of reactivation disease in people who are not infected with HIV (2) ; reactivation rates higher than 10% per annum have been reported in HIVinfected people (3) . The WHO estimates that in 2009 there were 9 . 4 million incident cases of active TB, 14 million prevalent cases of TB, 1 . 3 million deaths from TB in HIV-uninfected people and 0 . 38 million deaths from TB in HIV-infected people (4) . The development of new agents to prevent acquisition or reactivation of latent MTB infection and to allow shortening of antimicrobial therapy regimens for active TB without loss of efficacy is a research priority. This paper reviews the growing body of evidence from studies conducted both in vitro and in vivo suggesting that vitamin D might have a role in the prevention and treatment of TB.

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IFN-γ- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37

Cited by 49 publications

References 0 publications

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

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

Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

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

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IFN-γ- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37

Cited by 49 publications

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

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

Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

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

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

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