Immune response - IL-10 signaling pathway

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IL-10 signaling pathway

Interleukin-10 (IL-10) is a pleiotropic cytokine with important immunoregulatory functions. Its actions influence activities of many of the cell-types in the immune system. It is also a cytokine with potent anti-inflammatory properties: it represses the expression of inflammatory cytokines, such as Tumor necrosis factor-alpha (TNF-alpha), Interleukin-6 (IL-6) and Interleukin-1 (IL-1 beta), in macrophages [1], [2].

Functional IL-10 receptor complex is a tetramer consisting of two identical ligand-binding subunits (IL10RA) and two identical accessory signaling subunits (IL10RB) [3], [4], [5].

Binding of IL-10 to the extracellular domain of IL-10 receptor activates phosphorylation of the receptor-associated Janus kinase 1 (JAK1) and Tyrosine kinase 2 (Tyk2). These kinases then phosphorylate specific tyrosine residues on the intracellular domain of the IL-10 receptor. Once phosphorylated, these tyrosine residues serve as temporary docking sites for the latent transcription factor, Signal transducer and activator of transcription 3 (STAT3). STAT3 binds to these docking sites and is tyrosine-phosphorylated by the receptor-associated JAK1 and Tyk2. STAT3 then homodimerizes and translocates to the nucleus where it binds to the promoters of various IL-10-responsive genes [1], [6], [7].

STAT3 regulates transcription of anti-apoptotic genes, such as BCL2-like 1 (Bcl-XL) and B-cell CLL/lymphoma 2 (Bcl-2), and genes inhibiting cell cycle progression, such as Cyclin-dependent kinase inhibitor 2D (p19) [5], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

IL-10-induced STAT3 activation results in decreased expression of the inflammatory cytokines, such as TNF-alpha [2].

STAT3 also promotes transcription of Suppressor of cytokine signaling 3 (SOCS3). SOCS3 acts as a negative feedback regulator of IL-10/ JAK1/ STAT3 signaling and inhibits endotoxin-inducible expression of many inflammatory cytokines, including TNF-alpha, IL-6 and IL-1 beta [18], [19], [20], [21].

Interaction of IL-10 with IL-10 receptor also results in subsequent tyrosine-phosphorylation of STAT1 and, in non-macrophage cells, STAT5 [6], [22], [23], [24], [25]. In myeloid cells, IL-10 predominantly activates STAT3 and activated STAT3 is primarily involved in the negative regulation of macrophage activation [26]. The role of STAT1 and STAT5 in IL-10 signal transduction remains unclear, although IL-10-induced CD14 up-regulation in monocytes is believed to be mediated by STAT1 [1], [27].

IL-10 also stimulates tyrosine phosphorylation of Cysteine and glycine-rich protein 2 (CRP2), probably by JAK1, followed by rapid translocation of CRP2 into the nucleus where it up-regulates expression of the TIMP metallopeptidase inhibitor 1 (TIMP-1). TIMP-1 expression in human prostate cancer cells can play a key role in inhibiting tumor growth, perhaps by blocking tumor vascularization [28], [29].

IL-10 also activates another major survival pathway consisting of Insulin receptor substrate 2 (IRS-2), Phosphoinositide-3 kinase class IA (PI3K reg class IA/ PI3K cat class IA) and its downstream effectors 3-Phosphoinositide dependent protein kinase-1 (PDK (PDPK1)), Ribosomal protein S6 kinase 70kDa polypeptide 1 (p70S6K) and v-Akt murine thymoma viral oncogene homolog (AKT(PKB)) [1], [30], [31].

References:

  1. Williams LM, Ricchetti G, Sarma U, Smallie T, Foxwell BM
    Interleukin-10 suppression of myeloid cell activation--a continuing puzzle. Immunology 2004 Nov;113(3):281-92
  2. Hu X, Chen J, Wang L, Ivashkiv LB
    Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. Journal of leukocyte biology 2007 Aug;82(2):237-43
  3. Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW
    Expression cloning and characterization of a human IL-10 receptor. Journal of immunology (Baltimore, Md. : 1950) 1994 Feb 15;152(4):1821-9
  4. Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S
    Identification and functional characterization of a second chain of the interleukin-10 receptor complex. The EMBO journal 1997 Oct 1;16(19):5894-903
  5. Donnelly RP, Dickensheets H, Finbloom DS
    The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 1999 Jun;19(6):563-73
  6. Finbloom DS, Winestock KD
    IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. Journal of immunology (Baltimore, Md. : 1950) 1995 Aug 1;155(3):1079-90
  7. Murray PJ
    The JAK-STAT signaling pathway: input and output integration. Journal of immunology (Baltimore, Md. : 1950) 2007 Mar 1;178(5):2623-9
  8. O'Farrell AM, Parry DA, Zindy F, Roussel MF, Lees E, Moore KW, Mui AL
    Stat3-dependent induction of p19INK4D by IL-10 contributes to inhibition of macrophage proliferation. Journal of immunology (Baltimore, Md. : 1950) 2000 May 1;164(9):4607-15
  9. Alas S, Bonavida B
    Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer research 2001 Jul 1;61(13):5137-44
  10. Lai R, Rassidakis GZ, Medeiros LJ, Leventaki V, Keating M, McDonnell TJ
    Expression of STAT3 and its phosphorylated forms in mantle cell lymphoma cell lines and tumours. The Journal of pathology 2003 Jan;199(1):84-9
  11. Alas S, Bonavida B
    Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research 2003 Jan;9(1):316-26
  12. Stassi G, Todaro M, Zerilli M, Ricci-Vitiani L, Di Liberto D, Patti M, Florena A, Di Gaudio F, Di Gesu G, De Maria R
    Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer research 2003 Oct 15;63(20):6784-90
  13. Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH, Freidkin I, Albeck M, Longo DL, Kalechman Y
    Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer research 2004 Mar 1;64(5):1843-52
  14. Kalechman Y, Gafter U, Weinstein T, Chagnac A, Freidkin I, Tobar A, Albeck M, Sredni B
    Inhibition of interleukin-10 by the immunomodulator AS101 reduces mesangial cell proliferation in experimental mesangioproliferative glomerulonephritis: association with dephosphorylation of STAT3. The Journal of biological chemistry 2004 Jun 4;279(23):24724-32
  15. Vega MI, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B
    Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004 Apr 29;23(20):3530-40
  16. Chang WL, Baumgarth N, Eberhardt MK, Lee CY, Baron CA, Gregg JP, Barry PA
    Exposure of myeloid dendritic cells to exogenous or endogenous IL-10 during maturation determines their longevity. Journal of immunology (Baltimore, Md. : 1950) 2007 Jun 15;178(12):7794-804
  17. Miura Y, Nishimura Y, Katsuyama H, Maeda M, Hayashi H, Dong M, Hyodoh F, Tomita M, Matsuo Y, Uesaka A, Kuribayashi K, Nakano T, Kishimoto T, Otsuki T
    Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells. Apoptosis : an international journal on programmed cell death 2006 Oct;11(10):1825-35
  18. Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F
    Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):6404-11
  19. Williams L, Bradley L, Smith A, Foxwell B
    Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. Journal of immunology (Baltimore, Md. : 1950) 2004 Jan 1;172(1):567-76
  20. Takagi H, Sanada T, Minoda Y, Yoshimura A
    [Regulation of cytokine and toll-like receptor signaling by SOCS family genes]. Nippon rinsho. Japanese journal of clinical medicine 2004 Dec;62(12):2189-96
  21. Murray PJ
    Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Current opinion in pharmacology 2006 Aug;6(4):379-86
  22. Lai CF, Ripperger J, Morella KK, Jurlander J, Hawley TS, Carson WE, Kordula T, Caligiuri MA, Hawley RG, Fey GH, Baumann H
    Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements. The Journal of biological chemistry 1996 Jun 14;271(24):13968-75
  23. Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM
    IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS letters 1996 Oct 7;394(3):365-70
  24. Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD
    Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. The Journal of biological chemistry 1996 Nov 1;271(44):27954-61
  25. Yamaoka K, Otsuka T, Niiro H, Nakashima H, Tanaka Y, Nagano S, Ogami E, Niho Y, Hamasaki N, Izuhara K
    Selective DNA-binding activity of interleukin-10-stimulated STAT molecules in human monocytes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 1999 Jun;19(6):679-85
  26. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A
    Interleukin-10 and the interleukin-10 receptor. Annual review of immunology 2001;19:683-765
  27. Rahimi AA, Gee K, Mishra S, Lim W, Kumar A
    STAT-1 mediates the stimulatory effect of IL-10 on CD14 expression in human monocytic cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Jun 15;174(12):7823-32
  28. Wang M, Hu Y, Shima I, Stearns ME
    IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines. Cancer biology & therapy 2002 Sep-Oct;1(5):556-63
  29. Stearns ME, Hu Y, Wang M
    IL-10 signaling via IL-10E1 is dependent on tyrosine phosphorylation in the IL-10R alpha chain in human primary prostate cancer cell lines. Oncogene 2003 Jun 12;22(24):3781-91
  30. Crawley JB, Williams LM, Mander T, Brennan FM, Foxwell BM
    Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine. The Journal of biological chemistry 1996 Jul 5;271(27):16357-62
  31. Zhou JH, Broussard SR, Strle K, Freund GG, Johnson RW, Dantzer R, Kelley KW
    IL-10 inhibits apoptosis of promyeloid cells by activating insulin receptor substrate-2 and phosphatidylinositol 3'-kinase. Journal of immunology (Baltimore, Md. : 1950) 2001 Oct 15;167(8):4436-42

  1. Williams LM, Ricchetti G, Sarma U, Smallie T, Foxwell BM
    Interleukin-10 suppression of myeloid cell activation--a continuing puzzle. Immunology 2004 Nov;113(3):281-92
  2. Hu X, Chen J, Wang L, Ivashkiv LB
    Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. Journal of leukocyte biology 2007 Aug;82(2):237-43
  3. Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW
    Expression cloning and characterization of a human IL-10 receptor. Journal of immunology (Baltimore, Md. : 1950) 1994 Feb 15;152(4):1821-9
  4. Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S
    Identification and functional characterization of a second chain of the interleukin-10 receptor complex. The EMBO journal 1997 Oct 1;16(19):5894-903
  5. Donnelly RP, Dickensheets H, Finbloom DS
    The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 1999 Jun;19(6):563-73
  6. Finbloom DS, Winestock KD
    IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. Journal of immunology (Baltimore, Md. : 1950) 1995 Aug 1;155(3):1079-90
  7. Murray PJ
    The JAK-STAT signaling pathway: input and output integration. Journal of immunology (Baltimore, Md. : 1950) 2007 Mar 1;178(5):2623-9
  8. O'Farrell AM, Parry DA, Zindy F, Roussel MF, Lees E, Moore KW, Mui AL
    Stat3-dependent induction of p19INK4D by IL-10 contributes to inhibition of macrophage proliferation. Journal of immunology (Baltimore, Md. : 1950) 2000 May 1;164(9):4607-15
  9. Alas S, Bonavida B
    Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer research 2001 Jul 1;61(13):5137-44
  10. Lai R, Rassidakis GZ, Medeiros LJ, Leventaki V, Keating M, McDonnell TJ
    Expression of STAT3 and its phosphorylated forms in mantle cell lymphoma cell lines and tumours. The Journal of pathology 2003 Jan;199(1):84-9
  11. Alas S, Bonavida B
    Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research 2003 Jan;9(1):316-26
  12. Stassi G, Todaro M, Zerilli M, Ricci-Vitiani L, Di Liberto D, Patti M, Florena A, Di Gaudio F, Di Gesu G, De Maria R
    Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer research 2003 Oct 15;63(20):6784-90
  13. Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH, Freidkin I, Albeck M, Longo DL, Kalechman Y
    Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer research 2004 Mar 1;64(5):1843-52
  14. Kalechman Y, Gafter U, Weinstein T, Chagnac A, Freidkin I, Tobar A, Albeck M, Sredni B
    Inhibition of interleukin-10 by the immunomodulator AS101 reduces mesangial cell proliferation in experimental mesangioproliferative glomerulonephritis: association with dephosphorylation of STAT3. The Journal of biological chemistry 2004 Jun 4;279(23):24724-32
  15. Vega MI, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B
    Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004 Apr 29;23(20):3530-40
  16. Chang WL, Baumgarth N, Eberhardt MK, Lee CY, Baron CA, Gregg JP, Barry PA
    Exposure of myeloid dendritic cells to exogenous or endogenous IL-10 during maturation determines their longevity. Journal of immunology (Baltimore, Md. : 1950) 2007 Jun 15;178(12):7794-804
  17. Miura Y, Nishimura Y, Katsuyama H, Maeda M, Hayashi H, Dong M, Hyodoh F, Tomita M, Matsuo Y, Uesaka A, Kuribayashi K, Nakano T, Kishimoto T, Otsuki T
    Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells. Apoptosis : an international journal on programmed cell death 2006 Oct;11(10):1825-35
  18. Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F
    Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):6404-11
  19. Williams L, Bradley L, Smith A, Foxwell B
    Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. Journal of immunology (Baltimore, Md. : 1950) 2004 Jan 1;172(1):567-76
  20. Takagi H, Sanada T, Minoda Y, Yoshimura A
    [Regulation of cytokine and toll-like receptor signaling by SOCS family genes]. Nippon rinsho. Japanese journal of clinical medicine 2004 Dec;62(12):2189-96
  21. Murray PJ
    Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Current opinion in pharmacology 2006 Aug;6(4):379-86
  22. Lai CF, Ripperger J, Morella KK, Jurlander J, Hawley TS, Carson WE, Kordula T, Caligiuri MA, Hawley RG, Fey GH, Baumann H
    Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements. The Journal of biological chemistry 1996 Jun 14;271(24):13968-75
  23. Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM
    IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS letters 1996 Oct 7;394(3):365-70
  24. Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD
    Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. The Journal of biological chemistry 1996 Nov 1;271(44):27954-61
  25. Yamaoka K, Otsuka T, Niiro H, Nakashima H, Tanaka Y, Nagano S, Ogami E, Niho Y, Hamasaki N, Izuhara K
    Selective DNA-binding activity of interleukin-10-stimulated STAT molecules in human monocytes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 1999 Jun;19(6):679-85
  26. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A
    Interleukin-10 and the interleukin-10 receptor. Annual review of immunology 2001;19:683-765
  27. Rahimi AA, Gee K, Mishra S, Lim W, Kumar A
    STAT-1 mediates the stimulatory effect of IL-10 on CD14 expression in human monocytic cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Jun 15;174(12):7823-32
  28. Wang M, Hu Y, Shima I, Stearns ME
    IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines. Cancer biology & therapy 2002 Sep-Oct;1(5):556-63
  29. Stearns ME, Hu Y, Wang M
    IL-10 signaling via IL-10E1 is dependent on tyrosine phosphorylation in the IL-10R alpha chain in human primary prostate cancer cell lines. Oncogene 2003 Jun 12;22(24):3781-91
  30. Crawley JB, Williams LM, Mander T, Brennan FM, Foxwell BM
    Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine. The Journal of biological chemistry 1996 Jul 5;271(27):16357-62
  31. Zhou JH, Broussard SR, Strle K, Freund GG, Johnson RW, Dantzer R, Kelley KW
    IL-10 inhibits apoptosis of promyeloid cells by activating insulin receptor substrate-2 and phosphatidylinositol 3'-kinase. Journal of immunology (Baltimore, Md. : 1950) 2001 Oct 15;167(8):4436-42

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