title: Mycobacterium bovis bacillus Calmette-Guérin infection promotes SOCS induction and inhibits IFN-gamma-stimulated JAK/STAT signaling in J774 macrophages.
abstract: The resurgence in mycobacterial infection worldwide has led to renewed attention to the pathogenesis of Mycobacterium species. Although interferon-gamma (IFN-gamma) is a principal mediator of macrophage activation, macrophages infected with Mycobacterium are poor in response at the cytokine. However, the molecular mechanisms underlying mycobacterial infection remain unclear. The purpose of this study was to elucidate the mechanism of the poor response to IFN-gamma in mycobacterial infection. Our data clearly demonstrate that this is due to induction of suppressor of cytokine signal (SOCS) negative regulators of IFN-gamma signal transduction that closely correlates with the inhibition of JAK/STAT signaling and gene expression stimulated by IFN-gamma. Mycobacterium bovis bacillus Calmette-Guérin infection induces the production of SOCS-1 and SOCS-3 in murine J774 macrophages. The level of SOCS-1 mRNA increased 1 h and reached a maximum 3 h after the addition of the bacteria. SOCS-3 mRNA expression appeared as early as 1 h after the infection. We also observed that trehalose 6,6'-dimycolate/cord factor, a major component of the Mycobacterium tuberculosis cell wall, induces expression of SOCS and inhibits IFN-gamma-stimulated phosphorylation of STAT1 extensively in the cells. The results in this study suggest that a molecular mechanism of mycobacterial infection affects the unresponsiveness to IFN-gamma in the subsequent growth and spread of macrophages.
authors: Department of Oral Microbiology, Meikai University, School of Dentistry, Keyakidai, Sakado-shi, 350-0283, Saitama, Japan.
authors: Kenichi
authors: K
authors: Imai
authors: Tomoko
authors: T
authors: Kurita-Ochiai
authors: Kuniyasu
authors: K
authors: Ochiai
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D003311:Cord Factors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D009163:Mycobacterium bovis / Q000472:pathogenicity*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000302:isolation & purification / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D003311:Cord Factors; C485969:Cxcl9 protein, mouse; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2