title: Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells.
abstract: Mycobacterium tuberculosis survives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrict M. tuberculosis to latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by which M. tuberculosis modulates host responses to promote its survival remain unclear. In these studies, we demonstrate that M. tuberculosis induction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion of Tpl2 blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate that M. tuberculosis regulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway in Tpl2(-/-) macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4(+) T cells responding to M. tuberculosis infection. These data indicate that M. tuberculosis and its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Medical Scientist Training Program, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Medical Scientist Training Program, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Sweet
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Wearsch
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA Division of Infectious Diseases and HIV Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA cvh3@cwru.edu.
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005802:Genes, MHC Class II / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000502:physiology*; D051195:Toll-Like Receptor 2
chemical_list: C492236:Cdk5r1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D018664:Interleukin-12; D010770:Phosphotransferases; D048049:Extracellular Signal-Regulated MAP Kinases