Immune response - IL-1 signaling pathway

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IL-1 signaling pathway

Interleukin-1 (IL-1) is a proinflammatory cytokine produced by activated macrophages, endothelial cells, B cells and fibroblasts. IL-1 stimulates a broad spectrum of immune and inflammatory responses [1], [2].

There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 induces cellular response through its receptor composed of two subunits, Interleukin 1 receptor type I (IL-1RI) and Interleukin 1 receptor accessory protein (IL1RAP) [3], [4].

Activated by binding of either of its ligands IL-1 alpha and IL-1 beta, IL-1RI binds to the adaptor protein Myeloid differentiation primary response gene 88 (MyD88) that activates Interleukin-1 receptor-associated kinase 4 (IRAK4) and Interleukin-1 receptor-associated kinase 1 (IRAK1). The adaptor protein Toll interacting protein (TOLLIP) forms a complex with IRAK1 in resting cells and inhibits IL-1-induced signaling by blocking IRAK1 phosphorylation [5], [6], [7]. IRAK4 phosphorylates and activates IRAK1. The latter subsequently associates with TNF receptor-associated factor 6 (TRAF6) causing oligomerization and activation of TRAF6 that stimulates two distinct signaling pathways leading to the activation of transcription factors Nuclear factor kappa-B (NF-kB p50/p65) and Activator protein 1 (AP-1) [1], [7].

TRAF6 is a ubiquitin ligase (E3) that functions with the ubiquitin conjugating (E2) complex consisting of Ubiquitin-conjugating enzyme E2 variant 1 (UEV1A) and Ubiquitin-conjugating enzyme E2N (UBC13) to catalyze the synthesis of Lys63-linked polyubiquitin chains on target proteins including TRAF6 itself. Ubiquitinated TRAF6 then forms a complex with Mitogen-activated protein kinase kinase kinase 7 interacting proteins 1 and 2 (TAB1 and TAB2) and Mitogen-activated protein kinase kinase kinase 7 (TAK1). TAK1 phosphorylates the Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase beta (IKK-beta), a subunit of the Inhibitor of kB kinase complex (IKK complex). IKK complex is composed of one regulatory subunit, Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase gamma (IKK-gamma), and two catalytic subunits, Conserved helix-loop-helix ubiquitous kinase (IKK-alpha) and IKK-beta, forming the IKK complex catalytic core (IKK (cat)) [8], [9].

TAK1 also phosphorylates and activates Mitogen-activated protein kinase kinase kinase 14 (NIK) that phosphorylates IKK-alpha and stimulates its activity [10].

IKK (cat) then phosphorylates the Inhibitor of NF-kB (I-kB), leading to its ubiquitylation and subsequent degradation. This allows NF-kB p50/p65 to translocate into the nucleus and induce the expression of Interferon regulatory factor 1 (IRF1), Heme oxygenase 1, Prostaglandin-endoperoxide synthase 2 (COX-2), Nitric oxide synthase 2A (iNOS), Coagulation factor III (Tissue factor) and proinflammatory cytokines, such as Tumor necrosis factor (TNF-alpha), Interleukin 6 (IL-6) and Interleukin 8 (IL-8) [7], [8], [9], [11], [12], [13], [14], [15], [16], [17].

Another signaling pathway, TRAF6/ ECSIT homolog (SITPEC)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1), activates both NF-kB p50/p65 and AP-1 [18].

TAK1 and MEKK1 are responsible for the phosphorylation and activation of mitogen-activated protein kinase kinases 3, 4 and 6 (MEK3, MEK4 and MEK6). The three MEKs phosphorylate and activate Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)) and Mitogen-activated protein kinase 14 (p38alpha) leading to phosphorylation of the AP-1 subunit, Jun oncogene (c-Jun) and activation of AP-1 transcription factors, including c-Jun homodimer (c-Jun/c-Jun) [7], [19], [20], [21], [22].

p38alpha also phosphorylates Signal transducer and activator of transcription 1 (STAT1) which up-regulates IRF1 expression. STAT1 and IRF1 are involved in iNOS expression [13], [19].

c-Jun-containing AP-1 complexes induce the expression of Heme oxygenase 1, F3, Endothelin-1, Plasminogen activator inhibitor-1 (PAI1), Ceruloplasmin and multiple cytokines, including TNF-alpha, IL-6 and IL-8. [19], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].

References:

  1. Dunne A, O'Neill LA
    The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Science's STKE : signal transduction knowledge environment 2003 Feb 25;2003(171):re3
  2. Subramaniam S, Stansberg C, Cunningham C
    The interleukin 1 receptor family. Developmental and comparative immunology 2004 May 3;28(5):415-28
  3. Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU
    The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). The Journal of biological chemistry 1997 Mar 21;272(12):7727-31
  4. Dinarello CA
    Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. The American journal of clinical nutrition 2006 Feb;83(2):447S-455S
  5. Zhang G, Ghosh S
    Negative regulation of toll-like receptor-mediated signaling by Tollip. The Journal of biological chemistry 2002 Mar 1;277(9):7059-65
  6. Martin MU, Wesche H
    Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochimica et biophysica acta 2002 Nov 11;1592(3):265-80
  7. O'Neill LA
    Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Current topics in microbiology and immunology 2002;270:47-61
  8. Wullaert A, Heyninck K, Janssens S, Beyaert R
    Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Trends in immunology 2006 Nov;27(11):533-40
  9. Watters TM, Kenny EF, O'Neill LA
    Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunology and cell biology 2007 Aug-Sep;85(6):411-9
  10. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K
    The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 1999 Mar 18;398(6724):252-6
  11. Wickremasinghe MI, Thomas LH, Friedland JS
    Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. Journal of immunology (Baltimore, Md. : 1950) 1999 Oct 1;163(7):3936-47
  12. Dinarello CA
    The IL-1 family and inflammatory diseases. Clinical and experimental rheumatology 2002 Sep-Oct;20(5 Suppl 27):S1-13
  13. Lee SH, Nishino M, Mazumdar T, Garcia GE, Galfione M, Lee FL, Lee CL, Liang A, Kim J, Feng L, Eissa NT, Lin SH, Yu-Lee LY
    16-kDa prolactin down-regulates inducible nitric oxide synthase expression through inhibition of the signal transducer and activator of transcription 1/IFN regulatory factor-1 pathway. Cancer research 2005 Sep 1;65(17):7984-92
  14. Markovic M, Stuhlmeier KM
    Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like synoviocytes by blocking the activation of the transcription factor NF-kappaB. Journal of molecular medicine (Berlin, Germany) 2006 Oct;84(10):821-32
  15. Kuldo JM, Westra J, Asgeirsdottir SA, Kok RJ, Oosterhuis K, Rots MG, Schouten JP, Limburg PC, Molema G
    Differential effects of NF-{kappa}B and p38 MAPK inhibitors and combinations thereof on TNF-{alpha}- and IL-1{beta}-induced proinflammatory status of endothelial cells in vitro. American journal of physiology. Cell physiology 2005 Nov;289(5):C1229-39
  16. Nam NH
    Naturally occurring NF-kappaB inhibitors. Mini reviews in medicinal chemistry 2006 Aug;6(8):945-51
  17. Newton R, Holden NS, Catley MC, Oyelusi W, Leigh R, Proud D, Barnes PJ
    Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IkappaB kinase inhibitors. The Journal of pharmacology and experimental therapeutics 2007 May;321(2):734-42
  18. Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S
    ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes & development 1999 Aug 15;13(16):2059-71
  19. Guan Z, Buckman SY, Springer LD, Morrison AR
    Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1beta in rat glomerular mesangial cells. The Journal of biological chemistry 1999 Dec 17;274(51):36200-6
  20. Hagemann C, Blank JL
    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
  21. Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, Tamura S
    Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). The Journal of biological chemistry 2003 Apr 4;278(14):12013-21
  22. Symons A, Beinke S, Ley SC
    MAP kinase kinase kinases and innate immunity. Trends in immunology 2006 Jan;27(1):40-8
  23. Arts J, Grimbergen J, Bosma PJ, Rahmsdorf HJ, Kooistra T
    Role of c-Jun and proximal phorbol 12-myristate-13-acetate-(PMA)-responsive elements in the regulation of basal and PMA-stimulated plasminogen-activator inhibitor-1 gene expression in HepG2. European journal of biochemistry / FEBS 1996 Oct 15;241(2):393-402
  24. Lee ME, Dhadly MS, Temizer DH, Clifford JA, Yoshizumi M, Quertermous T
    Regulation of endothelin-1 gene expression by Fos and Jun. The Journal of biological chemistry 1991 Oct 5;266(28):19034-9
  25. Terry CM, Clikeman JA, Hoidal JR, Callahan KS
    Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. The American journal of physiology 1998 Mar;274(3 Pt 2):H883-91
  26. Daffada AA, Young SP
    Coordinated regulation of ceruloplasmin and metallothionein mRNA by interleukin-1 and copper in HepG2 cells. FEBS letters 1999 Aug 27;457(2):214-8
  27. Suzuki M, Tetsuka T, Yoshida S, Watanabe N, Kobayashi M, Matsui N, Okamoto T
    The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-alpha- or IL-1beta-stimulated rheumatoid synovial fibroblasts. FEBS letters 2000 Jan 7;465(1):23-7
  28. Chung HW, Wen Y, Ahn JJ, Moon HS, Polan ML
    Interleukin-1beta regulates urokinase plasminogen activator (u-PA), u-PA receptor, soluble u-PA receptor, and plasminogen activator inhibitor-1 messenger ribonucleic acid expression in cultured human endometrial stromal cells. The Journal of clinical endocrinology and metabolism 2001 Mar;86(3):1332-40
  29. Granchi S, Brocchi S, Bonaccorsi L, Baldi E, Vinci MC, Forti G, Serio M, Maggi M
    Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. The Prostate 2001 Dec 1;49(4):267-77
  30. Granchi S, Vannelli GB, Vignozzi L, Crescioli C, Ferruzzi P, Mancina R, Vinci MC, Forti G, Filippi S, Luconi M, Ledda F, Maggi M
    Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells. Molecular human reproduction 2002 Dec;8(12):1053-64
  31. Kietzmann T, Samoylenko A, Immenschuh S
    Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. The Journal of biological chemistry 2003 May 16;278(20):17927-36
  32. Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN
    The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proceedings of the National Academy of Sciences of the United States of America 2004 Feb 24;101(8):2434-9
  33. Lee CM, Lo HW, Shao RP, Wang SC, Xia W, Gershenson DM, Hung MC
    Selective activation of ceruloplasmin promoter in ovarian tumors: potential use for gene therapy. Cancer research 2004 Mar 1;64(5):1788-93
  34. Ishii H, Fujii T, Hogg JC, Hayashi S, Mukae H, Vincent R, van Eeden SF
    Contribution of IL-1 beta and TNF-alpha to the initiation of the peripheral lung response to atmospheric particulates (PM10). American journal of physiology. Lung cellular and molecular physiology 2004 Jul;287(1):L176-83
  35. Zhang Y, Adner M, Cardell LO
    Interleukin-1beta attenuates endothelin B receptor-mediated airway contractions in a murine in vitro model of asthma: roles of endothelin converting enzyme and mitogen-activated protein kinase pathways. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2004 Sep;34(9):1480-7
  36. Min KS, Kwon YY, Lee HJ, Lee SK, Kang KH, Lee SK, Kim EC
    Effects of proinflammatory cytokines on the expression of mineralization markers and heme oxygenase-1 in human pulp cells. Journal of endodontics 2006 Jan;32(1):39-43

  1. Dunne A, O'Neill LA
    The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Science's STKE : signal transduction knowledge environment 2003 Feb 25;2003(171):re3
  2. Subramaniam S, Stansberg C, Cunningham C
    The interleukin 1 receptor family. Developmental and comparative immunology 2004 May 3;28(5):415-28
  3. Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU
    The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). The Journal of biological chemistry 1997 Mar 21;272(12):7727-31
  4. Dinarello CA
    Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. The American journal of clinical nutrition 2006 Feb;83(2):447S-455S
  5. Zhang G, Ghosh S
    Negative regulation of toll-like receptor-mediated signaling by Tollip. The Journal of biological chemistry 2002 Mar 1;277(9):7059-65
  6. Martin MU, Wesche H
    Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochimica et biophysica acta 2002 Nov 11;1592(3):265-80
  7. O'Neill LA
    Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Current topics in microbiology and immunology 2002;270:47-61
  8. Wullaert A, Heyninck K, Janssens S, Beyaert R
    Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Trends in immunology 2006 Nov;27(11):533-40
  9. Watters TM, Kenny EF, O'Neill LA
    Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunology and cell biology 2007 Aug-Sep;85(6):411-9
  10. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K
    The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 1999 Mar 18;398(6724):252-6
  11. Wickremasinghe MI, Thomas LH, Friedland JS
    Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. Journal of immunology (Baltimore, Md. : 1950) 1999 Oct 1;163(7):3936-47
  12. Dinarello CA
    The IL-1 family and inflammatory diseases. Clinical and experimental rheumatology 2002 Sep-Oct;20(5 Suppl 27):S1-13
  13. Lee SH, Nishino M, Mazumdar T, Garcia GE, Galfione M, Lee FL, Lee CL, Liang A, Kim J, Feng L, Eissa NT, Lin SH, Yu-Lee LY
    16-kDa prolactin down-regulates inducible nitric oxide synthase expression through inhibition of the signal transducer and activator of transcription 1/IFN regulatory factor-1 pathway. Cancer research 2005 Sep 1;65(17):7984-92
  14. Markovic M, Stuhlmeier KM
    Short-term hyperthermia prevents activation of proinflammatory genes in fibroblast-like synoviocytes by blocking the activation of the transcription factor NF-kappaB. Journal of molecular medicine (Berlin, Germany) 2006 Oct;84(10):821-32
  15. Kuldo JM, Westra J, Asgeirsdottir SA, Kok RJ, Oosterhuis K, Rots MG, Schouten JP, Limburg PC, Molema G
    Differential effects of NF-{kappa}B and p38 MAPK inhibitors and combinations thereof on TNF-{alpha}- and IL-1{beta}-induced proinflammatory status of endothelial cells in vitro. American journal of physiology. Cell physiology 2005 Nov;289(5):C1229-39
  16. Nam NH
    Naturally occurring NF-kappaB inhibitors. Mini reviews in medicinal chemistry 2006 Aug;6(8):945-51
  17. Newton R, Holden NS, Catley MC, Oyelusi W, Leigh R, Proud D, Barnes PJ
    Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IkappaB kinase inhibitors. The Journal of pharmacology and experimental therapeutics 2007 May;321(2):734-42
  18. Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S
    ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes & development 1999 Aug 15;13(16):2059-71
  19. Guan Z, Buckman SY, Springer LD, Morrison AR
    Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1beta in rat glomerular mesangial cells. The Journal of biological chemistry 1999 Dec 17;274(51):36200-6
  20. Hagemann C, Blank JL
    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
  21. Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, Tamura S
    Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). The Journal of biological chemistry 2003 Apr 4;278(14):12013-21
  22. Symons A, Beinke S, Ley SC
    MAP kinase kinase kinases and innate immunity. Trends in immunology 2006 Jan;27(1):40-8
  23. Arts J, Grimbergen J, Bosma PJ, Rahmsdorf HJ, Kooistra T
    Role of c-Jun and proximal phorbol 12-myristate-13-acetate-(PMA)-responsive elements in the regulation of basal and PMA-stimulated plasminogen-activator inhibitor-1 gene expression in HepG2. European journal of biochemistry / FEBS 1996 Oct 15;241(2):393-402
  24. Lee ME, Dhadly MS, Temizer DH, Clifford JA, Yoshizumi M, Quertermous T
    Regulation of endothelin-1 gene expression by Fos and Jun. The Journal of biological chemistry 1991 Oct 5;266(28):19034-9
  25. Terry CM, Clikeman JA, Hoidal JR, Callahan KS
    Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. The American journal of physiology 1998 Mar;274(3 Pt 2):H883-91
  26. Daffada AA, Young SP
    Coordinated regulation of ceruloplasmin and metallothionein mRNA by interleukin-1 and copper in HepG2 cells. FEBS letters 1999 Aug 27;457(2):214-8
  27. Suzuki M, Tetsuka T, Yoshida S, Watanabe N, Kobayashi M, Matsui N, Okamoto T
    The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-alpha- or IL-1beta-stimulated rheumatoid synovial fibroblasts. FEBS letters 2000 Jan 7;465(1):23-7
  28. Chung HW, Wen Y, Ahn JJ, Moon HS, Polan ML
    Interleukin-1beta regulates urokinase plasminogen activator (u-PA), u-PA receptor, soluble u-PA receptor, and plasminogen activator inhibitor-1 messenger ribonucleic acid expression in cultured human endometrial stromal cells. The Journal of clinical endocrinology and metabolism 2001 Mar;86(3):1332-40
  29. Granchi S, Brocchi S, Bonaccorsi L, Baldi E, Vinci MC, Forti G, Serio M, Maggi M
    Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. The Prostate 2001 Dec 1;49(4):267-77
  30. Granchi S, Vannelli GB, Vignozzi L, Crescioli C, Ferruzzi P, Mancina R, Vinci MC, Forti G, Filippi S, Luconi M, Ledda F, Maggi M
    Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells. Molecular human reproduction 2002 Dec;8(12):1053-64
  31. Kietzmann T, Samoylenko A, Immenschuh S
    Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. The Journal of biological chemistry 2003 May 16;278(20):17927-36
  32. Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN
    The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proceedings of the National Academy of Sciences of the United States of America 2004 Feb 24;101(8):2434-9
  33. Lee CM, Lo HW, Shao RP, Wang SC, Xia W, Gershenson DM, Hung MC
    Selective activation of ceruloplasmin promoter in ovarian tumors: potential use for gene therapy. Cancer research 2004 Mar 1;64(5):1788-93
  34. Ishii H, Fujii T, Hogg JC, Hayashi S, Mukae H, Vincent R, van Eeden SF
    Contribution of IL-1 beta and TNF-alpha to the initiation of the peripheral lung response to atmospheric particulates (PM10). American journal of physiology. Lung cellular and molecular physiology 2004 Jul;287(1):L176-83
  35. Zhang Y, Adner M, Cardell LO
    Interleukin-1beta attenuates endothelin B receptor-mediated airway contractions in a murine in vitro model of asthma: roles of endothelin converting enzyme and mitogen-activated protein kinase pathways. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2004 Sep;34(9):1480-7
  36. Min KS, Kwon YY, Lee HJ, Lee SK, Kang KH, Lee SK, Kim EC
    Effects of proinflammatory cytokines on the expression of mineralization markers and heme oxygenase-1 in human pulp cells. Journal of endodontics 2006 Jan;32(1):39-43

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