NDLI: Toll-like Receptor 2 and DC-SIGNR1 Differentially Regulate Suppressors of Cytokine Signaling 1 in Dendritic Cells during Mycobacterium tuberculosis Infection*

Content Provider	PubMed Central
Author	Srivastava, Varsha Manchanda, Mini Gupta, Shashank Singla, Rupak Behera, Digamber Das, Gobardhan Natarajan, Krishnamurthy
Abstract	A hallmark of protective immunity during Mycobacterium tuberculosis (M. tb) infection is the regulated secretion of pro-inflammatory and regulatory cytokines. Suppressors of Cytokine Signaling (SOCS) are key regulators of cytokine secretion and function. In this study we investigated regulation of Toll-like receptor 2 (TLR2) and dendritic cell-specific ICAM-3 grabbing non-integrin receptor 1 (DC-SIGNR1)-mediated SOCS1 expression in DCs during M. tb infection. We show that, compared with TLR2, stimulating DC-SIGNR1 on DCs induces higher SOCS1 expression and lower interleukin-12 production. Co-stimulating DC-SIGNR1 and TLR2 differentially regulates SOCS1 expression depending on the relative concentration of their ligands. Stimulating DC-SIGNR1 with M. tb infection increases SOCS1 expression, while stimulating TLR2 with M. tb infection reduces SOCS1 expression. Knockdown of SOCS1 in DCs by siRNA enhances interleukin-12 transcription and protein expression upon DC-SIGNR1 stimulation. Raf-1 and Syk differentially regulate TLR2- and DC-SIGNR1-mediated SOCS1 expression. In addition, DC-SIGNR1 shows greater association with SOCS1 when compared with TLR2. Interestingly, compared with healthy asymptomatic individuals, peripheral blood mononuclear cells of patients with active tuberculosis disease showed higher expression of SOCS1, which was reduced following chemotherapy. Similarly, stimulating DC-SIGNR1 on DCs from M. tb-infected TLR2−/− mice enhanced SOCS1 expression that was reduced following chemotherapy. Further, knockdown of SOCS1 in mouse DCs or human peripheral blood mononuclear cells resulted in increased killing of virulent M. tb. These results indicate that TLR2 and DC-SIGNR1 differentially regulate SOCS1 expression during M. tb infection. This in turn regulates M. tb survival by governing key cytokine expression.
Related Links	http://dx.doi.org/10.1074/jbc.M109.006221
Starting Page	25532
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	38
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-09-18
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Toll-like Receptor 2 and DC-SIGNR1 Differentially Regulate Suppressors of Cytokine Signaling 1 in Dendritic Cells during Mycobacterium tuberculosis Infection

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Toll-like Receptor 2 and DC-SIGNR1 Differentially Regulate Suppressors of Cytokine Signaling 1 in Dendritic Cells during Mycobacterium tuberculosis Infection*

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