PDGF and the Small Inducible Gene (SIG) Family: Roles in the Inflammatory Response

  • Rodney S. Kawahara
  • Zheng-Wen Deng
  • Thomas F. Deuel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 305)


Inflammation and tissue repair involve a series of highly regulated and coordinated reactions that are beginning to be recognized and understood. Molecules ordinarily within intracellular compartments such as the platelet α-granule are released and appear to interact with target cells to initiate cell migration and division (1). The release of these factors and their interaction with cells stimulates a second wave of events through the transcriptional activation of genes which encode proteins with additional signalling roles (2,3). Inflammatory cells have been identified in close proximity to platelets in models of inflammation and immune complex disease and in lesions of atherosclerosis (4–8). These findings suggest close interactions and exchange of signals between platelets and inflammatory cells that mutually stimulate the release of these signalling molecules and initiate subsequent transcriptional events for the synthesis of additional mediators of inflammation and wound repair. Platelets may therefore play a central role in inflammation and tissue repair.


Glucocorticoid Receptor Platelet Factor Macrophage Inflammatory Protein Glucocorticoid Response Element Platelet Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Deuel, T. F. 1987. Polypeptide growth factors: Roles in normal and abnormal cell growth. Ann. Rev. Cell. Biol. 3: 443–492.PubMedCrossRefGoogle Scholar
  2. 2.
    Deuel, T. F., N. J. Silverman and R. S. Kawahara. 1988. Platelet-derived growth factor: a multifunctional regulator of normal and abnormal cell growth. Biofactors 1: 213–217.PubMedGoogle Scholar
  3. 3.
    Rollins, B. J. and C. D. Stiles. 1989. Serum-inducible genes. Advan. Can. Res. 53: 1–32.CrossRefGoogle Scholar
  4. 4.
    Senior, R. M., G. L. Griffin, A. Kimura, J. S. Huang and T. F. Deuel. 1989 Platelet α-granule protein-induced Chemotaxis of inflammatory cells and fibroblasts. Meth. Enzymol. 169: 233–244.PubMedCrossRefGoogle Scholar
  5. 5.
    Packham, M. A. and J. F. Mustard 1986. The role of platelets in the development and complications of atherosclerosis. Sem. Hematol. 23: 8–26.Google Scholar
  6. 6.
    Devreotes, P. N., and S. H. Zigmond. 1988. Chemotaxis in eukaryotic cells: a focus on leukocytes and dictyostelium. Ann. Rev. Cell. Biol. 4: 649–686.PubMedCrossRefGoogle Scholar
  7. 7.
    Wilkinson, P. C., 1982 Chemotaxis and Inflammation, Churchill Livingstone, New York.Google Scholar
  8. 8.
    Nachman, R. L. and B. Weksler. 1980. The Cell Biology of Inflammation (G. Weissmann, ed.), p. 145. Elsevier/North Holland, New York.Google Scholar
  9. 9.
    Deuel, T. F., R. M. Senior, D. Chang, G. L. Griffin, R. L. Heinrikson and E. T. Kaiser. 1981. Platelet factor 4 is chemotactic for neutrophils and monocytes. Proc. Natl. Acad. Sci. USA 78: 4584–4587.PubMedCrossRefGoogle Scholar
  10. 10.
    Osterman, D. G., G. L. Griffin, R. M. Senior, E. T. Kaiser, and T. F. Deuel. 1982. The carboxyl-terminal tridecapeptide of platelet factor 4 is a potent chemotactic agent for monocytes. Biochem. Biophys. Res. Comm. 107: 130–135.PubMedCrossRefGoogle Scholar
  11. 11.
    Senior, R. M., G. L. Griffin, J. S. Huang, D. A. Walz, and T. F. Deuel. 1983. Chemotactic activity of platelet alpha granule proteins for fibroblasts. J. Cell. Biol. 96: 382–385.PubMedCrossRefGoogle Scholar
  12. 12.
    Deuel, T. F., R. M. Senior, J. S. Huang, and G. L. Griffin. 1982. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J. Clin. Invest. 89:1046–1049.CrossRefGoogle Scholar
  13. 13.
    Grotendorst, G. R., H. E. J. Seppa, H. K. Kleinman, and G. R. Martin. 1981. Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 78: 3669–3672.PubMedCrossRefGoogle Scholar
  14. 14.
    Seppa, H., G. Grotendorst, S. Seppa, E. Schiffmann, and G. R. Martin. 1982. Platelet-derived growth factor is chemotactic for fibroblasts. J. Cell. Biol. 93: 584–588.CrossRefGoogle Scholar
  15. 15.
    Siegbahn, A., A. Hammacher, B. Westermark and C.-H. Heldin. 1990. Differential effects of the various isoforms of platelet-derived growth factor on Chemotaxis of fibroblasts, monocytes and granulocytes. J. Clin. Invest. 85: 916–920.PubMedCrossRefGoogle Scholar
  16. 16.
    Tzeng, D. Y., T. F. Deuel, J. S. Huang, R. M. Senior, L. A. Boxer, and R.L. Baehner. 1984. Platelet-derived growth factor promotes polymorphonuclear leukocyte activation. Blood 64: 1123–1128.PubMedGoogle Scholar
  17. 17.
    Tzeng, D. Y., T. F. Deuel, J. S. Huang, and R. L. Baehner. 1985. Platelet-derived growth factor promotes human peripheral monocyte activation. Blood 66: 179–183.PubMedGoogle Scholar
  18. 18.
    Bauer, E. A., T. W. Cooper, J. S. Huang, J. Altman and T. F. Deuel. 1985. Stimulation of in vitro human skin coUagenase expression by platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 82: 4132–4136.PubMedCrossRefGoogle Scholar
  19. 19.
    Gross, J. 1976 Biochemistry of Collagen (G. N. Ramachandran and A. H. Reddi, eds), p. 275. Plenum, New York.Google Scholar
  20. 20.
    Pierce, G. F., T. A. Mustoe, J. Lingelbach, V. R. Masakowski, P. Gramates and T. F. Deuel. 1989. Transforming growth factor β reverses the glucocorticoid-induced wound-healing deficit in rats: Possible regulation in macrophages by platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 86: 2229–2233.PubMedCrossRefGoogle Scholar
  21. 21.
    Pierce, G. F., T. A. Mustoe, J. Lingelbach, V. R. Masakowski, G. L. Griffin, R. M. Senior and T. F. Deuel. 1989. Platelet-derived growth factor and transforming growth factor-β enhance tissue repair activities by unique mechanisms. J. Cell. Biol. 109: 429PubMedCrossRefGoogle Scholar
  22. 22.
    Cochran, B. H., A. C. Reffel, and C. D. Stiles. 1983. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell 33: 939–947.PubMedCrossRefGoogle Scholar
  23. 23.
    Kohase, M., L. T. May, I. Tamm, J. Vilcek, and P. B. Sehgal. 1987. A cytokine network in human diploid fibroblasts: interaction β-interferons, tumor necrosis factor, platelet-derived growth factor, and interleukin-1. Mol. Cell Biol. 7: 273–280.PubMedGoogle Scholar
  24. 24.
    Rollins, B. J., E. D. Morrison, and C. D. Stiles. 1988. Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties. Proc. Natl. Acad. Sci. USA 85: 3738–3742.PubMedCrossRefGoogle Scholar
  25. 25.
    Kawahara, R. S. and T. F. Deuel. 1989. Platelet-derived growth factor inducible gene JE is a member of a family of small inducible genes related to platelet factor 4. J. Biol. Chem. 264: 679–682.PubMedGoogle Scholar
  26. 26.
    Timmer, H. T. M., G. J. Pronk, J. L. Bos, and A. J. van der Eb. 1990. Analysis of the rat JE gene promoter identifies an AP-1 binding site essential for basal expression but not for TPA induction. Nuc. Acids. Res. 18: 23–34.CrossRefGoogle Scholar
  27. 27.
    Yoshimura, T., N. Yuhki, S. K. Moore, E. Appella, M. I. Lerman, and E. J. Leonard. 1989. Human monocyte chemoattractant protein-1 (MCP-1) full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett. 244: 487–493.CrossRefGoogle Scholar
  28. 28.
    Furutani, H. Nomura, M. Notake, Y. Oyamada, T. Fukui, M. Yamada, C. G. Larsen, J. J. Oppenheim, and K. Matsushima. 1989. Cloning and sequencing of the cDNA for human monocyte chemotactic an activating factor (MCAF). Biochem. Biophys. Res. Comm. 159: 249–255.PubMedCrossRefGoogle Scholar
  29. 29.
    Decock, B., R. Conings, J.-P. Lenaerts, A. Billiau, and J. Van Damme. 1990. Identification of the monocyte chemotactic protein from human osteosarcoma cells and monocytes: detection of a novel N-terminally processed form. Biochem. Biophys. Res. Comm. 167: 904–909.PubMedCrossRefGoogle Scholar
  30. 30.
    Chang, H. C., F. Hsu, G. J. Freeman, J. D. Griffin, and E. L. Reinherz. 1989. Cloning and expression of a gamma-interferon inducible gene in monocytes: a new member of a cytokine gene family. Inter. Immunol. 1: 388–397.CrossRefGoogle Scholar
  31. 31.
    Graves, D. T, Y. L. Jiang, M. J. Williamson, and A. J. Valente. 1989. Identification of monocyte chemotactic activity produced by malignant cells. Science 245: 1490–1493.PubMedCrossRefGoogle Scholar
  32. 32.
    Rollins, B. J., P. Stier, T. Ernst, and G. G. Wong. 1989. The human homolog of the JE gene encodes a monocyte secretory protein. Mol. Cell. Biol. 9: 4687–4695.PubMedGoogle Scholar
  33. 33.
    Yoshimura, T., E. A. Robinson, S. Tanaka, E. Appella, and E. J. Leonard. 1989. Purification and amino acid analysis of two human monocyte chemoattractant produced by phytohemag-glutinin-stimulated human blood mononuclear leukocytes. J. Immunol. 142: 1956–1962.PubMedGoogle Scholar
  34. 34.
    Obaru, K., M. Fukuda, S. Maeda, and K. Shimada. 1986. A cDNA clone used to study mRNA inducible in human tonsillar lymphocytes by a tumor promoter. J. Biochem. 99: 885–894.PubMedGoogle Scholar
  35. 35.
    Nakao, M., H. Nomiyama, and K. Shimada. 1990. Structures of human genes coding for cytokine LD78 and their expression. Mol. Cell. Biol. 10: 3646–3658.PubMedGoogle Scholar
  36. 36.
    Davatelis, G., P. Tekamp-Olson, S. D. Wolpe, K. Hermsen, C. Luedke, C. Gallegos, D. Coit, J. Merryweather, and A. Cerami. 1988. Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties. J. Exper. Med. 167: 1939–1944.CrossRefGoogle Scholar
  37. 37.
    Sherry, B., P. Tekamp-Olson, C. Gallegos, D. Bauer, G. Davateliks, S. D. Wolpe, F. Masiarz, D. Coit, and A. Cerami. 1988. Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1β. J. Exper. Med. 168: 2251–2259.CrossRefGoogle Scholar
  38. 38.
    Chang, H. C., and E. L. Reinherz. 1989. Isolation and characterization of a cDNA encoding a putative cytokine which is induced by stimulation via the CD2 structure on human T lymphocytes. Eur. J. Immunol. 19: 1045–1051.PubMedCrossRefGoogle Scholar
  39. 39.
    Lipes, M. A., M Napolitano, K.-T. Jeang, N. T. Chang, and W. J. Leonard. 1988. Identification, cloning and characterization of an immune activation gene. Proc. Natl Acad. Sci. USA 85: 9704–9708.PubMedCrossRefGoogle Scholar
  40. 40.
    Brown, K. D., S. M. Zurawski, T. R. Mosmann and G. Zurawski. 1989. A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors and indicators of various activation processes. J. Immunol. 142: 679–687.PubMedGoogle Scholar
  41. 41.
    Schall, T. J., J. Jongstra, B. J. Dyer, J. Jorgensen, C. Clayberger, M. M. Davis and A. M. Krensky. 1988. A human T cell-specific molecule is a member of a new gene family. J. Immunol. 141: 1013–1025.Google Scholar
  42. 42.
    Burd, P. A., G. J. Freeman, S. D. Wilson, M. Berman, R. DeKruyff, P. R. Billings and M. E. Dorf. 1987. Cloning and characterization of a novel T cell activation gene. J. Immunol. 138: 3126–3131.Google Scholar
  43. 43.
    Zipfel, P. F., J. Balke, S. G. Irving, K. Kelly and U. Siebenlist. 1989. Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors. J. Immunol. 142: 1582–1590.PubMedGoogle Scholar
  44. 44.
    Luster, A. D., J. C. Unkeless, and J. V. Ravetch. 1985. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315: 672–676.PubMedCrossRefGoogle Scholar
  45. 45.
    Luster, A. D. and J. V. Ravetch. 1987. Genomic characterization of a gamma-interferon inducible gene (IP-10) and identification of an interferon-inducible hypersensitive site, Mol. Cell. Biol. 7: 3723–3731.PubMedGoogle Scholar
  46. 46.
    Matsushima, K., K. Morishita, T. Yoshimura, S. Lavu, Y. Kobayashi, W. Lew, E. Appella, H. F. Kung, E. J. Leonard, and J. J. Oppenheim. 1988. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J. Exper. Med. 167: 1883–1893.CrossRefGoogle Scholar
  47. 47.
    Mukaida, N., M. Shiroo, and K. Matsushima. 1989. Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. J. Immunol. 143: 1366–1371.PubMedGoogle Scholar
  48. 48.
    Deuel, T. F., P. S. Keim, M. Farmer, and R. L. Heinrikson. 1977. Amino acid sequence of human platelet factor 4. Proc. Natl Acad. Sci. USA 74: 2256–2258.PubMedCrossRefGoogle Scholar
  49. 49.
    Poncz, M., S. Surrey, P. LaRocco, M. J. Weiss, E. F. Rappaport, T. M. Conway, and E. Schwartz, Cloning and characterization of platelet factor 4 cDNA derived from a human erythroleukemic cell line. Blood 69: 219–223.Google Scholar
  50. 50.
    Holt, J. C., M. E. Harris, A. M. Holt, E. Lange, A. Henschen, and S. Niewiarowski, Characterization of human platelet basic protein, a precursor form of low-affinity platelet factor 4 and β-thromboglobulin. Biochemistry 25: 1988–1996.Google Scholar
  51. 51.
    Doi, T., S. M. Greenberg, R. D. Rosenberg, Structure of the rat platelet factor 4 gene: a marker for megakaryocyte differentiation. Mol. Cell. Biol. 7: 898–904.Google Scholar
  52. 52.
    Green,C. J., R. St. Charles, B. F. P. Edwards, and P. H. Johnson. 1989. Identification and characterization of PF4varl, a human gene variant of platelet factor 4. Mol. Cell. Biol. 9: 1445–1451.PubMedGoogle Scholar
  53. 53.
    Wenger, R. H., A. N. Wicki, A. Walz, N. Kieffer, and K. J. Clemetson. 1989. Cloning of cDNA coding for connective tissue activating peptide III from a human platelet-derived gtll expression library Blood 73: 1498–1503.PubMedGoogle Scholar
  54. 54.
    Begg, G. S., D. S. Pepper, C. N. Chesterman, and F. J. Morgan. 1978. Complete covalent structure of human β-thromboglobulin. Biochemistry 17: 1739–1744.PubMedCrossRefGoogle Scholar
  55. 55.
    Walz, A., and M. Baggiolini, A novel cleavage product of β-thromboglobulin formed in cultures of stimulated mononuclear cells activates human neutrophils. Biochem. Biophys. Res. Comm. 159: 969–975.Google Scholar
  56. 56.
    Anisowicz, A., L. Bardwell, and R. Sager. 1987. Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc. Natl Acad. Sci. USA 84: 7188–7192.PubMedCrossRefGoogle Scholar
  57. 57.
    Richmond, A., E. Balentien, H. G. Thomas, G. Flaggs, D. E. Barton, J. Spiess, R. Bordoni, U. Francke, and R. Derynck. 1988. Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to β-thromboglobulin. EMBO J. 7:2025–2033.PubMedGoogle Scholar
  58. 58.
    Oquendo, P., J. Alberta, D. Wen, J. L. Graycar, R. Derynck, and C. D. Stiles. 1989. The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet α-granule proteins. J. Biol. Chem. 264: 4133–4137.PubMedGoogle Scholar
  59. 59.
    Watanabe, K., K. Konishi, M. Fujioka, S. Kinoshita, and H. Nakagawa. 1989. The neutrophil chemoattractant produced by the rat kidney epithelioid cell line NRK-52E is a protein related to the KC/gro protein. J. Biol. Chem. 264: 19559–19563.PubMedGoogle Scholar
  60. 60.
    Bedard, P.-A., D. Alcorta, D. L. Simmons, K.-C. Luk, and R. L. Erikson. 1987. Constitutive expression of a gene encoding a polypeptide homologous to biologically active human platelet protein in Rous sarcoma virus-transformed fibroblasts. Proc. Natl. Acad. Sci. USA 84: 6715–6719.PubMedCrossRefGoogle Scholar
  61. 61.
    Sugano, S., M. Y., Stoeckle, and H. Hanafusa. 1987. Transformation by Rous sarcoma virus induces a novel gene with homology to a mitogenic platelet protein. Cell 49: 321–328.PubMedCrossRefGoogle Scholar
  62. 62.
    Martins-Green, M., and M. J. Bissell. 1990. Localization of 9E3/CEF-4 in avian tissues: Expression is absent in rous sarcoma virus but is stimulated by injury. J. Cell. Biol. 110: 581–595.PubMedCrossRefGoogle Scholar
  63. 63.
    Wolpe, S. D., B. Sherry, D. Juers, G. Davatelis, R. W. Yurt and A. Cerami. 1989. Identification and characterization of macrophage inflammatory protein 2. Proc. Natl. Acad. Sci. USA 86: 612–616.PubMedCrossRefGoogle Scholar
  64. 64.
    Modi, W. S., M. Dean, H. N. Seuanez, N. Mukaida, K. Matsushima and S. J. O’Brien. 1990. Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily. Hum. Genet. 84: 185–187.PubMedCrossRefGoogle Scholar
  65. 65.
    Wolpe, S. D. and A. Cerami. 1989. Macrophage inflammatory proteins 1 and 2: members of a novel superfamily of cytokines. FASEB J. 3: 2565–2573.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Rodney S. Kawahara
    • 1
  • Zheng-Wen Deng
    • 1
  • Thomas F. Deuel
    • 1
    • 2
  1. 1.Department of MedicineJewish Hospital at Washington University Medical CenterLouisUSA
  2. 2.Department of Biochemistry/Molecular BiophysicsJewish Hospital at Washington University Medical CenterLouisUSA

Personalised recommendations