Secretion of cytokines by human macrophages upon infection by pathogenic and non-pathogenic mycobacteria

Beltan, Eric; Horgen, Lionel; Rastogi, Nalin

doi:10.1006/mpat.1999.0345

Cited by 97 publications

(86 citation statements)

References 20 publications

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“…Beltan et al [20], who found that macrophages infected with non-pathogenic mycobacteria (M. smegmatis and M. phlei) secreted higher amounts of these cytokines than the infected with M. tuberculosis. In neutrophils, mycobacteria did not induce, or at very low leves, the production of any cytokine, with the exception of IL-8, which were similarly induced by all three mycobacteria.…”

Section: Discussionmentioning

confidence: 99%

Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria

2008

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Non-pathogenic mycobacteria, like Mycobacterium gordonae, are rarely associated to disease. The analysis of the mechanisms which are successful against them in the human host may provide useful information to understand why they fail against the pathogenic M. tuberculosis. We have developed an infection model in human phagocytes to test their ability to kill two strains of M. gordonae , HL184Gand an attenuated variety, HL184Gat. As controls we included a strain of M. tuberculosis (HL186T) and another of L. pneumophila (ATCC13151). We observed that human phagocytes lack the intrinsic ability to eliminate either M. gordonae or M. tuberculosis, but they kill the attenuated strain. We could observe a relationship between pathogenicity and the pattern of cytokine production. Thus, both the pathogenic M. tuberculosis and L. pneumophila, but not the nonpathogenic M. gordonae, induced the production of significantly different levels of IL-1β, IL-6 and TNF-α in monocytes and IL-8 in neutrophils. Although both monocytes and neutrophils killed HL184Gat, but not HL184G, the patterns of cytokine production induced by either strain were identical. Addition of INF-γ and/or TNF-α did not improve the antimycobacterial activity of phagocytes.

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Section: Discussionmentioning

confidence: 99%

Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria

2008

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“…Although several studies have demonstrated that mycobacteria are able to dampen or subvert the innate immune response (13,14,17), the molecular mechanism underlying this phenomenon is still largely unknown. Our previous results have indicated that the ESX-5 secretion system might be responsible for a defect in the M infection cycle (26).…”

Section: Discussionmentioning

confidence: 99%

“…These cytokines include TNF-␣, which plays a key role in granuloma formation (10,11), , and IL-12, a pivotal cytokine in the host defense against mycobacteria (8,(13)(14)(15). One of the mechanisms used by mycobacteria to modify M functional properties is their ability to manipulate the secretion of proinflammatory cytokines (16,17). Exactly how pathogenic mycobacteria are able to subvert cytokine responses, however, is still unclear.…”

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confidence: 99%

The ESX-5 Secretion System of Mycobacterium marinum Modulates the Macrophage Response

Abdallah

Savage

Zon

et al. 2008

The Journal of Immunology

129

110

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The ESX-5 secretion system of pathogenic mycobacteria is responsible for the secretion of various PPE and PE-PGRS proteins. To better understand the role of ESX-5 effector proteins in virulence, we analyzed the interactions of Mycobacterium marinum ESX-5 mutant with human macrophages (Mφ). Both wild-type bacteria and the ESX-5 mutant were internalized and the ESX-5 mutation did not affect the escape of mycobacteria from phagolysosomes into the cytosol, as was shown by electron microscopy. However, the ESX-5 mutation strongly effected expression of surface Ags and cytokine secretion. Whereas wild-type M. marinum actively suppressed the induction of appreciable levels of IL-12p40, TNF-α, and IL-6, infection with the ESX-5 mutant resulted in strongly induced production of these proinflammatory cytokines. By contrast, infection with M. marinum wild-type strain resulted in a significant induction of IL-1β production as compared with the ESX-5 mutant. These results show that ESX-5 plays an essential role in the modulation of immune cytokine secretion by human Mφ. Subsequently, we show that an intact ESX-5 secretion system actively suppresses TLR signaling-dependent innate immune cytokine secretion. Together, our results show that ESX-5 substrates, directly or indirectly, strongly modulate the human Mφ response at various critical steps.

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“…Pathogenic mycobacteria have been shown to induce less TNF than nonpathogenic mycobacteria in human macrophages (27). The regulation of expression and secretion of TNF by pathogenic mycobacteria is likely a key factor in modulating the host cell immune response.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosislipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

Rajaram

Morris

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

258

221

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Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPKactivated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3′ UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/ Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.lipoglycans | innate immunity | cell signaling | intracellular pathogen

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Secretion of cytokines by human macrophages upon infection by pathogenic and non-pathogenic mycobacteria

Cited by 97 publications

References 20 publications

Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria

Human phagocytes lack the ability to kill Mycobacterium gordonae, a non-pathogenic mycobacteria

The ESX-5 Secretion System of Mycobacterium marinum Modulates the Macrophage Response

Mycobacterium tuberculosislipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

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