2015
DOI: 10.1189/jlb.3a1114-557r
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Role for NOD2 in Mycobacterium tuberculosis-induced iNOS expression and NO production in human macrophages

Abstract: M.tb, which causes TB, is a host-adapted intracellular pathogen of macrophages. Macrophage intracellular PRRs, such as NOD proteins, regulate proinflammatory cytokine production in response to various pathogenic organisms. We demonstrated previously that NOD2 plays an important role in controlling the inflammatory response and viability of M.tb and Mycobacterium bovis BCG in human macrophages. Various inflammatory mediators, such as cytokines, ROS, and RNS, such as NO, can mediate this control. iNOS (or NOS2) … Show more

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Cited by 50 publications
(31 citation statements)
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References 55 publications
(70 reference statements)
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“…It is important to note, however, that the extent and nature of interplay between the NOS2 and IDO1 pathway may significantly differ between mice and humans, which probably relates to a species differential with respect to the expression of these different enzymes in response to inflammatory stimuli. As indicated above, whereas IFNγ and LPS are potent stimuli of murine NOS2 expression, expression of NOS2 in human innate immune cells is subject to more tight regulation requiring stimulation by combinations of cytokines and inflammatory stimuli or microbial infection, and, when expressed, is generally at considerably lower levels when compared with NOS2 expression in murine counterparts [7,195]. Similarly, human cells express IDO1 in response to IFNγ and LPS to a markedly greater extent than their murine counterparts.…”
Section: •−mentioning
confidence: 89%
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“…It is important to note, however, that the extent and nature of interplay between the NOS2 and IDO1 pathway may significantly differ between mice and humans, which probably relates to a species differential with respect to the expression of these different enzymes in response to inflammatory stimuli. As indicated above, whereas IFNγ and LPS are potent stimuli of murine NOS2 expression, expression of NOS2 in human innate immune cells is subject to more tight regulation requiring stimulation by combinations of cytokines and inflammatory stimuli or microbial infection, and, when expressed, is generally at considerably lower levels when compared with NOS2 expression in murine counterparts [7,195]. Similarly, human cells express IDO1 in response to IFNγ and LPS to a markedly greater extent than their murine counterparts.…”
Section: •−mentioning
confidence: 89%
“…Moreover, although there are reports of human APCs expressing NOS isoforms (e.g. [195,196]), controversy exists with respect to the relative levels of production and the biological ramifications of NOS-derived NO produced by human innate and adaptive immune cells [197][198][199][200]. Therefore, although co-expression of IDO1 and NOS are noted in certain human and murine tissues in vivo in response to infection and inflammation [7], caution is required in readily extrapolating murine data on the interplay between NOS2 and IDO1 to the human situation.…”
Section: •−mentioning
confidence: 96%
“…RIP2 then recruits and activates the transforming growth factor beta-activated kinase 1 (TAK1) complex to mediate the downstream signaling including MAPK and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) which in turn orchestrate NOD2-induced immune responses (18,19). NOD2 activation translates to the expression of several immunomodulators like cyclooxygenase (COX)-2 (20), suppressor of cytokine signaling (SOCS)-3 (21), matrix metalloproteinase (MMP)-9 (22), inducible nitric-oxide synthase catalyzed NO (23), cytokines like TNF-␣ (10, 24), VEGF-A (25), and IL-12 (24,26). While NO and cytokines like TNF-␣, IL-12 mediate the NOD2-responsive pro-inflammatory responses, COX-2, SOCS-3, MMP-9, and VEGF-A constitutes the anti-inflammatory arm of the NOD2 responses.…”
mentioning
confidence: 99%
“…In contrast, in cultured human macrophages, monocytes and DCs infected with H37Rv, a study which rekindled interest in the use of Vitamin D supplementation as an adjunctive therapy showed that TLR2 signalling, in combination with Vitamin D3, upregulates expression of cathelecidin which co-localises with the phagosome to kill the bacilli in an iNOS-independent manner [69]. Recently, iNOS has been shown to be regulated by the NOD2 PRR in human MDM infected with BCG and H37Rv [265,277] identifying NOD2 as a potential target of host directed therapies.…”
Section: Macrophagesmentioning
confidence: 99%