Coordinating TLR‐activated signaling pathways in cells of the immune system

Toll‐like receptor (TLR) signaling leads to the activation of mitogen‐activated protein kinase and nuclear factor‐κB signaling pathways. While the upstream signaling events initiated at the level of adaptors and the activation of the downstream signaling pathways have received a lot of attention, our understanding of how these signaling pathways are coordinated to regulate gene expression is poorly understood. This review gives a selective overview on our current understanding of signaling downstream of TLRs, with an emphasis on how the upstream kinases like the mitogen‐activated protein kinase kinase kinases (TAK1 and Tpl2) and inhibitor of κ‐B kinase (IKK) coordinate the signaling events that steer the course of an immune response.

[1]  L. Johnston,et al.  TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. , 1999, Nature.

[2]  Bali Pulendran,et al.  Translating Innate Immunity into Immunological Memory: Implications for Vaccine Development , 2006, Cell.

[3]  Ruslan Medzhitov,et al.  Toll-Like Receptor Signaling Pathways , 2003, Science.

[4]  P. Tsichlis,et al.  Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Ruslan Medzhitov,et al.  Control of B-cell responses by Toll-like receptors , 2005, Nature.

[6]  C. Scheidereit,et al.  NF‐κB p105 is a target of IκB kinases and controls signal induction of Bcl‐3–p50 complexes , 1999 .

[7]  C. Scheidereit,et al.  Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. , 2001, Molecular and cellular biology.

[8]  P. Blackshear,et al.  Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin , 1998 .

[9]  S. Howell,et al.  ABIN-2 Forms a Ternary Complex with TPL-2 and NF-κB1 p105 and Is Essential for TPL-2 Protein Stability , 2004, Molecular and Cellular Biology.

[10]  P. Blackshear,et al.  Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. , 1998, Science.

[11]  Shao-Cong Sun,et al.  Phosphorylation of NF-kappaB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation. , 2006, Biochimica et biophysica acta.

[12]  L. Johnston,et al.  TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105 , 1999, Nature.

[13]  S. Akira,et al.  TLR signaling. , 2006, Current topics in microbiology and immunology.

[14]  C. Scheidereit,et al.  Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα , 2001, Molecular and Cellular Biology.

[15]  J. Peli,et al.  Involvement of the Tpl-2/cot oncogene in MMTV tumorigenesis. , 1996, Oncogene.

[16]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[17]  L. O’Neill,et al.  The expanding family of MyD88-like adaptors in Toll-like receptor signal transduction. , 2004, Molecular immunology.

[18]  L. Turka,et al.  The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. , 2006, Immunity.

[19]  D. Kioussis,et al.  ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses , 2006, Nature Immunology.

[20]  J. Dean,et al.  The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. , 2004, Cellular signalling.

[21]  B. Pulendran.  Variegation of the Immune Response with Dendritic Cells and Pathogen Recognition Receptors1 , 2005, The Journal of Immunology.

[22]  Gabriel Pineda,et al.  Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. , 2006, Molecular cell.

[23]  S. Smerdon,et al.  NF-κB1 p105 Negatively Regulates TPL-2 MEK Kinase Activity , 2003, Molecular and Cellular Biology.

[24]  入江 崇.  TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-κB in lipopolysaccharide-stimulated macrophages , 2000 .

[25]  I. Caramalho,et al.  Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide , 2003, The Journal of experimental medicine.

[26]  B. Pulendran,et al.  ERK1−/− Mice Exhibit Th1 Cell Polarization and Increased Susceptibility to Experimental Autoimmune Encephalomyelitis1 , 2006, The Journal of Immunology.

[27]  D. Ballard,et al.  Proteolytic processing of NF-kappa B/I kappa B in human monocytes. ATP-dependent induction by pro-inflammatory mediators. , 1995, The Journal of biological chemistry.

[28]  Jeonghee Cho,et al.  Induction of COX‐2 by LPS in macrophages is regulated by Tpl2‐dependent CREB activation signals , 2002, The EMBO journal.

[29]  K. Heeg,et al.  CpG‐oligodeoxynucleotides co‐stimulate primary T cells in the absence of antigen‐presenting cells , 1999, European journal of immunology.

[30]  R. Seth,et al.  Ubiquitin, TAK1 and IKK: is there a connection? , 2006, Cell Death and Differentiation.

[31]  Steve Gerondakis,et al.  Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[32]  B. Pulendran,et al.  Cutting Edge: Different Toll-Like Receptor Agonists Instruct Dendritic Cells to Induce Distinct Th Responses via Differential Modulation of Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase and c-Fos 1 , 2003, The Journal of Immunology.

[33]  J. Steitz,et al.  Overexpression of HuR, a nuclear–cytoplasmic shuttling protein, increases the in vivo stability of ARE‐containing mRNAs , 1998, The EMBO journal.

[34]  G. M. Wilson,et al.  Regulation of A + U-rich Element-directed mRNA Turnover Involving Reversible Phosphorylation of AUF1* , 2003, Journal of Biological Chemistry.

[35]  G. Kollias,et al.  TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. , 2000, Cell.

[36]  S. Saccani,et al.  p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. , 2002, Nature immunology.

[37]  R. Flavell,et al.  The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors , 2002, Nature.

[38]  N. Copeland,et al.  Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. , 1997, Genes & development.

[39]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[40]  Gary Brewer,et al.  Regulation of Cyclooxygenase 2 mRNA Stability by the Mitogen-Activated Protein Kinase p38 Signaling Cascade , 2000, Molecular and Cellular Biology.

[41]  A. Salmeron,et al.  Direct Phosphorylation of NF-κB1 p105 by the IκB Kinase Complex on Serine 927 Is Essential for Signal-induced p105 Proteolysis* , 2001, The Journal of Biological Chemistry.

[42]  Jeonghee Cho,et al.  Tpl2/Cot Signals Activate ERK, JNK, and NF-κB in a Cell-type and Stimulus-specific Manner* , 2005, Journal of Biological Chemistry.

[43]  J. Dean,et al.  p38 Mitogen-activated Protein Kinase Stabilizes mRNAs That Contain Cyclooxygenase-2 and Tumor Necrosis Factor AU-rich Elements by Inhibiting Deadenylation* , 2003, Journal of Biological Chemistry.

[44]  Margarida Saraiva,et al.  Identification of a Macrophage-Specific Chromatin Signature in the IL-10 Locus1 , 2005, The Journal of Immunology.

[45]  J. Gutkind,et al.  Multiple Mitogen-Activated Protein Kinase Signaling Pathways Connect the Cot Oncoprotein to the c-junPromoter and to Cellular Transformation , 2000, Molecular and Cellular Biology.

[46]  B. Pulendran,et al.  A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells 1 , 2004, The Journal of Immunology.

[47]  Shao-Cong Sun,et al.  NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. , 2003, Molecular cell.

[48]  A. Masuda,et al.  A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. , 2004, The Journal of clinical investigation.

[49]  R. Medzhitov,et al.  TIRAP: an adapter molecule in the Toll signaling pathway , 2001, Nature Immunology.

[50]  J. Ninomiya-Tsuji,et al.  The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway , 1999, Nature.

[51]  P. Tsichlis,et al.  The Tpl-2 protooncoprotein activates the nuclear factor of activated T cells and induces interleukin 2 expression in T cell lines. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  C. Dumitru,et al.  Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40 , 2003, The EMBO journal.

[53]  S. Howell,et al.  NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. , 2003, Molecular and cellular biology.

[54]  P. Cohen,et al.  Role of Mitogen-Activated Protein Kinase Cascades in Mediating Lipopolysaccharide-Stimulated Induction of Cyclooxygenase-2 and IL-1β in RAW264 Macrophages1 , 2000, The Journal of Immunology.

[55]  Shao-Cong Sun,et al.  IkappaB kinase is an essential component of the Tpl2 signaling pathway. , 2004, Molecular and cellular biology.

[56]  Shao-Cong Sun,et al.  IκB Kinase Is an Essential Component of the Tpl2 Signaling Pathway , 2004, Molecular and Cellular Biology.

[57]  L. Turka,et al.  Toll-Like Receptor Ligands Directly Promote Activated CD4+ T Cell Survival , 2004, The Journal of Immunology.

[58]  D. Ballard,et al.  Proteolytic Processing of NF-B/IB in Human Monocytes , 1995, The Journal of Biological Chemistry.

[59]  Weiyi Peng,et al.  Toll-Like Receptor 8-Mediated Reversal of CD4+ Regulatory T Cell Function , 2005, Science.

[60]  C. Figdor,et al.  How C‐type lectins detect pathogens , 2005, Cellular microbiology.

[61]  S. Akira,et al.  TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway , 2003, Nature Immunology.

[62]  H. Gascan,et al.  Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells1 , 2005, The Journal of Immunology.

[63]  Zhijian J. Chen,et al.  TAK1 is a ubiquitin-dependent kinase of MKK and IKK , 2001, Nature.

[64]  S. Gerondakis,et al.  Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models , 2006, Oncogene.

[65]  D. Pappin,et al.  Activation of MEK‐1 and SEK‐1 by Tpl‐2 proto‐oncoprotein, a novel MAP kinase kinase kinase. , 1996, The EMBO journal.

[66]  P. Godowski,et al.  Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and Cytokines , 2002, The Journal of Immunology.

[67]  P. Blackshear,et al.  Necrosis Factor Alpha Mrna Deadenylation and Destabilization of Tumor Au-rich Elements and Promotes the Evidence That Tristetraprolin Binds To , 1999 .

[68]  G. Kollias,et al.  TNF-α Induction by LPS Is Regulated Posttranscriptionally via a Tpl2/ERK-Dependent Pathway , 2000, Cell.

[69]  B. Haynes,et al.  A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. , 1996, Immunity.

[70]  S. Saccani,et al.  p38-dependent marking of inflammatory genes for increased NF-κB recruitment , 2002, Nature Immunology.

[71]  K. Mahtani,et al.  The 3′ Untranslated Region of Tumor Necrosis Factor Alpha mRNA Is a Target of the mRNA-Stabilizing Factor HuR , 2001, Molecular and Cellular Biology.

[72]  J. Dean,et al.  Post‐transcriptional regulation of gene expression by mitogen‐activated protein kinase p38 , 2003, FEBS letters.