Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Krutzik, Stephan R.; Ochoa, María Teresa; Sieling, Peter A.; Uematsu, Satoshi; Ng, Yolanda W.; Legaspi, Annaliza; Liu, Philip T.; Cole, Stewart T.; Godowski, Paul J.; Maeda, Yosuke; Sarno, Euzenir Nunes; Norgard, Michael V.; Brennan, Patrick J.; Akira, Shizuo; Rea, Thomas H.; Modlin, Robert L.

doi:10.1038/nm864

Cited by 311 publications

(267 citation statements)

References 45 publications

Supporting

Mentioning

249

Contrasting

Unclassified

Order By: Relevance

“…Importantly, and confirming the in vivo relevance of theses findings, TLR2 expression on CD14 þ cells was lower in healthy volunteers with shorter alleles than in those without them. Although the promoter activities of constructs including GT repeats and expression of TLR2 on CD14 þ cells did not upregulate with LPS or whole lysates of M. tuberculosis in this study, the decrements of TLR2 expression on human cells by various stimulation 49 or during exposure to M. tuberculosis have been reported. 50 The essential role of TLR2 against mycobacterial infection in vivo has been shown by rapid fatality 28,29 and higher burden of mycobacteria 51 in TLR2-deficient mice.…”

Section: Discussioncontrasting

confidence: 69%

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

et al. 2006

View full text Add to dashboard Cite

The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT) 13 , (GT) 20 , and (GT) 24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14 þ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P ¼ 0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14 þ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats. Genes and Immunity (2006) 7, 150-155.

show abstract

Section: Discussioncontrasting

confidence: 69%

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Support for this hypothesis came from the fact that previous studies have demonstrated that the phagocytosis of P. falciparum-parasitized erythrocytes is enhanced by PPARc ligands without TNF-a production [11]. In addition, it has previously been shown that Th2 cytokines like IL-4 activate PPARc in Mu [18] while this cytokine down-regulates TLR2 expression [42], suggesting that TLR2 and PPARc are opposite signaling pathways.Here, we have provided evidence that IL-13 upregulates CD36 surface expression in human monocytes and increases CD36 mRNA. Our results demonstrate for the first time that IL-13 up-regulates CD36 via PPARc.…”

mentioning

confidence: 99%

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

et al. 2007

View full text Add to dashboard Cite

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

show abstract

“…Mature DCs migrate from the infected/inflamed tissue and enter lymphatic circulation, presumably directed by up-regulation of surface expression of CCR7, the only chemokine receptor expressed by mature DCs (5). M. leprae activates DCs via TLR2-TLR1 heterodimers, presumably through triacylated lipoproteins like the 19-kDa lipoprotein (6). TLR2 polymorphisms have been linked to increased susceptibility to leprosy (7,8).…”

mentioning

confidence: 99%

Mycobacterium leprae Inhibits Dendritic Cell Activation and Maturation

Murray¹,

Siddiqui

Mendillo

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Leprosy presents with a clinical spectrum of skin lesions that span from strong Th1-mediated cellular immunity and control of bacillary growth at one pole to poor Ag-specific T cell immunity with extensive bacillary load and Th2 cytokine-expressing lesions at the other. To understand how the immune response to Mycobacterium leprae is regulated, human dendritic cells (DC), potent inducers of adaptive immune responses, exposed to M. leprae, Mycobacterium tuberculosis (Mtb), and Mycobacterium bovis bacillus Calmette-Guerin (BCG) were studied for their ability to be activated and to prime T cell proliferation. In contrast with Mtb and BCG, M. leprae did not induce DC activation/maturation as measured by the expression of selected surface markers and proinflammatory cytokine production. In MLR, T cells did not proliferate in response to M. leprae-stimulated DC. Interestingly, M. leprae-exposed MLR cells secreted increased Th2 cytokines as well as similar Th1 cytokine levels as compared with Mtb- and BCG-exposed cells. Gene expression analysis revealed a reduction in levels of mRNA of DC activation and maturation markers following exposure to M. leprae. Our data suggest that M. leprae does not induce and probably suppresses in vitro DC maturation/activation, whereas Mtb and BCG are stimulatory.

show abstract

Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Cited by 311 publications

References 45 publications

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

Mycobacterium leprae Inhibits Dendritic Cell Activation and Maturation

Contact Info

Product

Resources

About