1α,25-Dihydroxyvitamin D3-induced Monocyte Antimycobacterial Activity Is Regulated by Phosphatidylinositol 3-Kinase and Mediated by the NADPH-dependent Phagocyte Oxidase

Sly, Laura M.; López, Martín; Nauseef, William M.; Reiner, Neil E.

doi:10.1074/jbc.m102876200

Cited by 223 publications

(173 citation statements)

References 60 publications

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“…Notably, NOX2-derived ROS production was required for the mRNA expression of cathelicidin and the subsequent antimycobacterial activities induced by 1,25D 3 -treated macrophages. Previous studies showed that the reactive oxygen intermediate scavenger 4-hydroxy-TEMPO, degradative enzymes, and polyethylene glycol coupled to superoxide dismutase or catalase abrogated 1,25D 3 -induced antimycobacterial activity, suggesting that 1,25D 3 -induced antimycobacterial activity is mediated by NOX in phagocytes (42). In human dendritic cells, NOX-derived oxygen radicals are not required for dendritic cell differentiation, maturation, cytokine production, or the induction of T cell proliferation; however, they are essential for intracellular bacterial killing (43).…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase 2 Interaction with TLR2 Is Required for Efficient Innate Immune Responses to Mycobacteria via Cathelicidin Expression

Yang

Shin

Kim

et al. 2009

The Journal of Immunology

170

160

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Gp91phox/NADPH oxidase (NOX) 2 is the main catalytic component of NOX, which mediates the phagocytic killing of ingested pathogens via the production of reactive oxygen species (ROS). However, Mycobacterium tuberculosis (Mtb) is relatively resistant to the microbicidal effects of ROS. Thus, the exact roles of NOX2 in the innate immune control against Mtb infection are not fully resolved. In this study, we show that NOX2 is essential for TLR2-dependent inflammatory responses and 1,25-dihydroxyvitamin D3 (1,25D3)-mediated antimicrobial activity against Mtb via cathelicidin expression. NOX2-null macrophages prominently abrogated Mtb-induced ROS production and inflammatory signaling activation in a TLR2-dependent manner. Mtb triggered a physical association between NOX2 and TLR2. In addition, the knockdown of NOX2 inhibited 1,25D3-triggered antimicrobial activity against viable Mtb through the modulation of cathelicidin expression in human macrophages. Treatment of NOX2 knocked down cells with cathelicidin restored the 1,25D3-induced antimicrobial effect, suggesting that the NOX2-dependent induction of cathelicidin in macrophages is part of a defensive strategy against Mtb. Furthermore, cathelicidin expression was required for the Mtb-induced release of ROS and the production of proinflammatory cytokines/chemokines, indicating a positive circuit of inflammation in response to Mtb. Our data collectively demonstrate a novel regulatory mechanism for TLR2-dependent innate responses to Mtb involving crosstalk between NOX2 and TLR2 and the expression of cathelicidin.

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Section: Discussionmentioning

confidence: 99%

NADPH Oxidase 2 Interaction with TLR2 Is Required for Efficient Innate Immune Responses to Mycobacteria via Cathelicidin Expression

Yang

Shin

Kim

et al. 2009

The Journal of Immunology

170

160

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“…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) .…”

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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“…The role of PI 3-K in mycobacterial phagocytosis was reported recently in macrophages [16]. In addition, the PI 3-K pathway plays an important role in human monocyte antimycobacterial activity [17] and up-regulates a signalling pathway involved in cell survival through lipoarabinomannan-mediated Bad phosphorylation [7].…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of interleukin-12 and tumour necrosis factor-α by phosphatidylinositol 3-kinase and ERK 1/2 pathways duringMycobacterium tuberculosisinfection

Yang

Lee

Jung

et al. 2005

Clinical and Experimental Immunology

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1α,25-Dihydroxyvitamin D3-induced Monocyte Antimycobacterial Activity Is Regulated by Phosphatidylinositol 3-Kinase and Mediated by the NADPH-dependent Phagocyte Oxidase

Cited by 223 publications

References 60 publications

NADPH Oxidase 2 Interaction with TLR2 Is Required for Efficient Innate Immune Responses to Mycobacteria via Cathelicidin Expression

NADPH Oxidase 2 Interaction with TLR2 Is Required for Efficient Innate Immune Responses to Mycobacteria via Cathelicidin Expression

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

Differential regulation of interleukin-12 and tumour necrosis factor-α by phosphatidylinositol 3-kinase and ERK 1/2 pathways duringMycobacterium tuberculosisinfection

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