Immune response - IL-5 signalling

print

Select Species:

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


IL-5 signaling

Interleukin 5 (colony-stimulating factor, eosinophil) (IL-5) is produced by Th2 cells and mast cells after activation by mitogens or antigens [1]. IL-5 is capable to induce the survival, growth and differentiation of eosinophils and B-cells [2].

IL-5 receptor is composed of two polypeptide chains: alpha and beta subunits. Both subunits contain extracellular domains. The alpha and beta subunits are associated only in the presence of ligand. Alpha-subunit is ligand-specific and beta subunit is shared with the receptors for Interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating-factor (GM-CSF) [3], [4].

Following IL-5 -induced hetero-dimerization, IL-5 receptor binds to multiple signal-transducing proteins, which include Janus kinase 1 (JAK1) and 2 (JAK2), v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn), spleen tyrosine kinase (Syk) and SHC transforming protein 1 (Shc). Lyn additionally phosphorylates Syk and Bruton agammaglobulinemia tyrosine kinase (Btk) [5], [6], [7], [8], [9], [10], [11].

Actvated JAK2 phosphorylates STAT1, STAT3 and STAT5, JAK1 also phosphorylates STAT5 [9], [12], [13]. Phosphorylated STAT5 and STAT3 translocate to the nucleus and activates transcription of different genes, including Pim-1 oncogene (Pim-1) and v-myc myelocytomatosis viral oncogene homolog (avian) (c-Myc), [13], [14], [15], [16]. Pim-1 and c-Myc play role in cell proliferation and survival processes [13], [17], [18]. STAT5 activity is necessary for cell differentiation [19]. Phosphorylation of STAT3 leads to increase of Cyclin D3 expression [13].

JAK2 also phosphorylates IL-5 receptor that leads to different signal pathways [7], [20].

Upon IL-5 stimulation, the adaptor molecule Shc is rapidly phosphorylated and associates with the phosphorylated IL-5 receptor. IL-5 stimulation also results in the activation of GRB2 and protein tyrosine phosphatase, non-receptor type 11 (SHP-2) which associates with Shc and form a complex with Son of sevenless homologs (SOS) [7], [21], [22], [23]. SOS promotes v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras )/ v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ ERK1/2 pathway [24], [25]. ERK1/2 activates phospholipase A2, group IV (cPLA2) that catalyses modification of Platelet activating factor to Lyso-PAF. Lyso-PAF enhances eosinophil adhesion through interacting with Integrin, alpha M (ITGAM) and Integrin, beta 2 (ITGB2) [26], [27]. ITGB2 directly binds to intercellular adhesion molecule 1 (ICAM1) [26].

Activation of ERK1/2 also leads to anti-apoptosis [25].

IL-5 induces not only JAK-dependent activation of STAT5, but a JAK-independent too. Shc binds to v-crk sarcoma virus CT10 oncogene homolog (avian)-like (CrkL) [28], that induces binding of CrkL to STAT5 [29].

CrkL activates Rap guanine nucleotide exchange factor (GEF) 1 (C3G). This leads to induction of RAP1A, member of RAS oncogene family (RAP-1A) [29].

Under IL-5 action, Lyn induces Phosphoinositide-3-kinase regulatory subunits (PI3K reg class IA (p85))/ Phosphoinositide-3-kinase catalytic subunits (PI3K cat class A1) [30]. PI3K cat class A1 catalyses PtdIns(3,4,5)P3 formation that leads to activation of v-akt murine thymoma viral oncogene homologs (AKT(PKB)) by direct interaction with PtdIns(3,4,5)P3 as well as by interaction with 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) induced by PtdIns(3,4,5)P3 [31]. This cascade possibly plays an important role in inhibition of apoptosis [20].

PI3K reg class IA (p85) also binds to Protein kinase C, delta (PKC-delta) [32]. Activated PKC-delta takes part in regulation of Ras/MEK/ERK pathway by interacting with c-Raf-1. This also induces integrin adhesion [33]. PKC-delta activates NADPH-oxidase that leads to oxygen generation and oxidative stress [34].

IL-5 through IL-5 receptor enhances expression of v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun oncogene (c-Jun) [35].

IL-5 increases expression of B-cell CLL/lymphoma 2 (Bcl-2) and jun B proto-oncogene (JunB) providing inhibition of apoptosis [18], [36].

References:

  1. Swain SL, McKenzie DT, Weinberg AD, Hancock W
    Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells. Journal of immunology (Baltimore, Md. : 1950) 1988 Nov 15;141(10):3445-55
  2. Kouro T, Takatsu K
    IL-5- and eosinophil-mediated inflammation: from discovery to therapy. International immunology 2009 Dec;21(12):1303-9
  3. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G
    A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell 1991 Sep 20;66(6):1175-84
  4. Murphy JM, Young IG
    IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitamins and hormones 2006;74:1-30
  5. Sato S, Katagiri T, Takaki S, Kikuchi Y, Hitoshi Y, Yonehara S, Tsukada S, Kitamura D, Watanabe T, Witte O, Takatsu K
    IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases. The Journal of experimental medicine 1994 Dec 1;180(6):2101-11
  6. Mui AL, Wakao H, Harada N, O'Farrell AM, Miyajima A
    Interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 transduce signals through two forms of STAT5. Journal of leukocyte biology 1995 May;57(5):799-803
  7. Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ, Ravichandran KS
    Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor. The Journal of biological chemistry 1996 May 24;271(21):12137-40
  8. Yousefi S, Hoessli DC, Blaser K, Mills GB, Simon HU
    Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. The Journal of experimental medicine 1996 Apr 1;183(4):1407-14
  9. Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T, Takatsu K
    JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation. Blood 1998 Apr 1;91(7):2264-71
  10. Stafford S, Lowell C, Sur S, Alam R
    Lyn tyrosine kinase is important for IL-5-stimulated eosinophil differentiation. Journal of immunology (Baltimore, Md. : 1950) 2002 Feb 15;168(4):1978-83
  11. Lee WH, Liu FH, Lin JY, Huang SY, Lin H, Liao WJ, Huang HM
    JAK pathway induction of c-Myc critical to IL-5 stimulation of cell proliferation and inhibition of apoptosis. Journal of cellular biochemistry 2009 Apr 1;106(5):929-36
  12. Erhardt I, Lischke A, Sebald W, Friedrich K
    Constitutive association of JAK1 and STAT5 in pro-B cells is dissolved by interleukin-4-induced tyrosine phosphorylation of both proteins. FEBS letters 1998 Nov 13;439(1-2):71-4
  13. Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ
    IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. Journal of immunology (Baltimore, Md. : 1950) 2004 Nov 15;173(10):6409-17
  14. Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T
    STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. The EMBO journal 1999 Sep 1;18(17):4754-65
  15. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T
    Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 1999 Dec;11(6):709-19
  16. Lord JD, McIntosh BC, Greenberg PD, Nelson BH
    The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2533-41
  17. Sakai I, Kraft AS
    The kinase domain of Jak2 mediates induction of bcl-2 and delays cell death in hematopoietic cells. The Journal of biological chemistry 1997 May 9;272(19):12350-8
  18. Juan SH, Yen JJ, Lee HM, Huang HM
    IL-5 inhibits apoptosis by upregulation of c-myc expression in human hematopoietic cells. Annals of the New York Academy of Sciences 2005 May;1042:481-7
  19. de Groot RP, Coffer PJ, Koenderman L
    Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cellular signalling 1998 Oct;10(9):619-28
  20. Dijkers PF, van Dijk TB, de Groot RP, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ
    Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene 1999 Jun 3;18(22):3334-42
  21. Pazdrak K, Adachi T, Alam R
    Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. The Journal of experimental medicine 1997 Aug 18;186(4):561-8
  22. Downward J
    Signal transduction. New exchange, new target. Nature 1998 Dec 3;396(6710):416-7
  23. Rane SG, Reddy EP
    JAKs, STATs and Src kinases in hematopoiesis. Oncogene 2002 May 13;21(21):3334-58
  24. Alam R, Pazdrak K, Stafford S, Forsythe P
    The interleukin-5/receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras-Raf-1-MAP kinase and the Jak-STAT pathways in eosinophils. International archives of allergy and immunology 1995 May-Jun;107(1-3):226-7
  25. Adachi T, Alam R
    The mechanism of IL-5 signal transduction. The American journal of physiology 1998 Sep;275(3 Pt 1):C623-33
  26. Zhu X, Subbaraman R, Sano H, Jacobs B, Sano A, Boetticher E, Muñoz NM, Leff AR
    A surrogate method for assessment of beta(2)-integrin-dependent adhesion of human eosinophils to ICAM-1. Journal of immunological methods 2000 Jun 23;240(1-2):157-64
  27. Zhu X, Jacobs B, Boetticher E, Myou S, Meliton A, Sano H, Lambertino AT, Muñoz NM, Leff AR
    IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2. Journal of leukocyte biology 2002 Nov;72(5):1046-53
  28. Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O
    Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochemical and biophysical research communications 1997 Oct 20;239(2):412-7
  29. Du J, Alsayed YM, Xin F, Ackerman SJ, Platanias LC
    Engagement of the CrkL adapter in interleukin-5 signaling in eosinophils. The Journal of biological chemistry 2000 Oct 20;275(42):33167-75
  30. Pigazzi A, Heydrick S, Folli F, Benoit S, Michelson A, Loscalzo J
    Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets. The Journal of biological chemistry 1999 May 14;274(20):14368-75
  31. Vanhaesebroeck B, Alessi DR
    The PI3K-PDK1 connection: more than just a road to PKB. The Biochemical journal 2000 Mar 15;346 Pt 3:561-76
  32. Sano M, Leff AR, Myou S, Boetticher E, Meliton AY, Learoyd J, Lambertino AT, Munoz NM, Zhu X
    Regulation of interleukin-5-induced beta2-integrin adhesion of human eosinophils by phosphoinositide 3-kinase. American journal of respiratory cell and molecular biology 2005 Jul;33(1):65-70
  33. Gliki G, Abu-Ghazaleh R, Jezequel S, Wheeler-Jones C, Zachary I
    Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+. The Biochemical journal 2001 Feb 1;353(Pt 3):503-12
  34. Woschnagg C, Venge P, Garcia RC
    The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. Cytokine 2004 Nov 7;28(3):137-48
  35. Takaki S, Kanazawa H, Shiiba M, Takatsu K
    A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Molecular and cellular biology 1994 Nov;14(11):7404-13
  36. Dewson G, Walsh GM, Wardlaw AJ
    Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5. American journal of respiratory cell and molecular biology 1999 Apr;20(4):720-8

  1. Swain SL, McKenzie DT, Weinberg AD, Hancock W
    Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells. Journal of immunology (Baltimore, Md. : 1950) 1988 Nov 15;141(10):3445-55
  2. Kouro T, Takatsu K
    IL-5- and eosinophil-mediated inflammation: from discovery to therapy. International immunology 2009 Dec;21(12):1303-9
  3. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G
    A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell 1991 Sep 20;66(6):1175-84
  4. Murphy JM, Young IG
    IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitamins and hormones 2006;74:1-30
  5. Sato S, Katagiri T, Takaki S, Kikuchi Y, Hitoshi Y, Yonehara S, Tsukada S, Kitamura D, Watanabe T, Witte O, Takatsu K
    IL-5 receptor-mediated tyrosine phosphorylation of SH2/SH3-containing proteins and activation of Bruton's tyrosine and Janus 2 kinases. The Journal of experimental medicine 1994 Dec 1;180(6):2101-11
  6. Mui AL, Wakao H, Harada N, O'Farrell AM, Miyajima A
    Interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 transduce signals through two forms of STAT5. Journal of leukocyte biology 1995 May;57(5):799-803
  7. Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ, Ravichandran KS
    Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor. The Journal of biological chemistry 1996 May 24;271(21):12137-40
  8. Yousefi S, Hoessli DC, Blaser K, Mills GB, Simon HU
    Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. The Journal of experimental medicine 1996 Apr 1;183(4):1407-14
  9. Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T, Takatsu K
    JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation. Blood 1998 Apr 1;91(7):2264-71
  10. Stafford S, Lowell C, Sur S, Alam R
    Lyn tyrosine kinase is important for IL-5-stimulated eosinophil differentiation. Journal of immunology (Baltimore, Md. : 1950) 2002 Feb 15;168(4):1978-83
  11. Lee WH, Liu FH, Lin JY, Huang SY, Lin H, Liao WJ, Huang HM
    JAK pathway induction of c-Myc critical to IL-5 stimulation of cell proliferation and inhibition of apoptosis. Journal of cellular biochemistry 2009 Apr 1;106(5):929-36
  12. Erhardt I, Lischke A, Sebald W, Friedrich K
    Constitutive association of JAK1 and STAT5 in pro-B cells is dissolved by interleukin-4-induced tyrosine phosphorylation of both proteins. FEBS letters 1998 Nov 13;439(1-2):71-4
  13. Stout BA, Bates ME, Liu LY, Farrington NN, Bertics PJ
    IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils. Journal of immunology (Baltimore, Md. : 1950) 2004 Nov 15;173(10):6409-17
  14. Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T
    STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. The EMBO journal 1999 Sep 1;18(17):4754-65
  15. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T
    Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 1999 Dec;11(6):709-19
  16. Lord JD, McIntosh BC, Greenberg PD, Nelson BH
    The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2533-41
  17. Sakai I, Kraft AS
    The kinase domain of Jak2 mediates induction of bcl-2 and delays cell death in hematopoietic cells. The Journal of biological chemistry 1997 May 9;272(19):12350-8
  18. Juan SH, Yen JJ, Lee HM, Huang HM
    IL-5 inhibits apoptosis by upregulation of c-myc expression in human hematopoietic cells. Annals of the New York Academy of Sciences 2005 May;1042:481-7
  19. de Groot RP, Coffer PJ, Koenderman L
    Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cellular signalling 1998 Oct;10(9):619-28
  20. Dijkers PF, van Dijk TB, de Groot RP, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ
    Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene 1999 Jun 3;18(22):3334-42
  21. Pazdrak K, Adachi T, Alam R
    Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival. The Journal of experimental medicine 1997 Aug 18;186(4):561-8
  22. Downward J
    Signal transduction. New exchange, new target. Nature 1998 Dec 3;396(6710):416-7
  23. Rane SG, Reddy EP
    JAKs, STATs and Src kinases in hematopoiesis. Oncogene 2002 May 13;21(21):3334-58
  24. Alam R, Pazdrak K, Stafford S, Forsythe P
    The interleukin-5/receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras-Raf-1-MAP kinase and the Jak-STAT pathways in eosinophils. International archives of allergy and immunology 1995 May-Jun;107(1-3):226-7
  25. Adachi T, Alam R
    The mechanism of IL-5 signal transduction. The American journal of physiology 1998 Sep;275(3 Pt 1):C623-33
  26. Zhu X, Subbaraman R, Sano H, Jacobs B, Sano A, Boetticher E, Muñoz NM, Leff AR
    A surrogate method for assessment of beta(2)-integrin-dependent adhesion of human eosinophils to ICAM-1. Journal of immunological methods 2000 Jun 23;240(1-2):157-64
  27. Zhu X, Jacobs B, Boetticher E, Myou S, Meliton A, Sano H, Lambertino AT, Muñoz NM, Leff AR
    IL-5-induced integrin adhesion of human eosinophils caused by ERK1/2-mediated activation of cPLA2. Journal of leukocyte biology 2002 Nov;72(5):1046-53
  28. Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O
    Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochemical and biophysical research communications 1997 Oct 20;239(2):412-7
  29. Du J, Alsayed YM, Xin F, Ackerman SJ, Platanias LC
    Engagement of the CrkL adapter in interleukin-5 signaling in eosinophils. The Journal of biological chemistry 2000 Oct 20;275(42):33167-75
  30. Pigazzi A, Heydrick S, Folli F, Benoit S, Michelson A, Loscalzo J
    Nitric oxide inhibits thrombin receptor-activating peptide-induced phosphoinositide 3-kinase activity in human platelets. The Journal of biological chemistry 1999 May 14;274(20):14368-75
  31. Vanhaesebroeck B, Alessi DR
    The PI3K-PDK1 connection: more than just a road to PKB. The Biochemical journal 2000 Mar 15;346 Pt 3:561-76
  32. Sano M, Leff AR, Myou S, Boetticher E, Meliton AY, Learoyd J, Lambertino AT, Munoz NM, Zhu X
    Regulation of interleukin-5-induced beta2-integrin adhesion of human eosinophils by phosphoinositide 3-kinase. American journal of respiratory cell and molecular biology 2005 Jul;33(1):65-70
  33. Gliki G, Abu-Ghazaleh R, Jezequel S, Wheeler-Jones C, Zachary I
    Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+. The Biochemical journal 2001 Feb 1;353(Pt 3):503-12
  34. Woschnagg C, Venge P, Garcia RC
    The effect of IL-5 treatment on the stimulation-induced phosphorylation of proteins in blood eosinophils. Cytokine 2004 Nov 7;28(3):137-48
  35. Takaki S, Kanazawa H, Shiiba M, Takatsu K
    A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Molecular and cellular biology 1994 Nov;14(11):7404-13
  36. Dewson G, Walsh GM, Wardlaw AJ
    Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5. American journal of respiratory cell and molecular biology 1999 Apr;20(4):720-8

Target Details

Click on a target from the pathway image to view related information.