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J Clin Invest. Nov 15, 1996; 98(10): 2403–2413.
PMCID: PMC507693

Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44.

Abstract

Hyaluronan (HA) is a glycosaminoglycan constituent of extracellular matrix. In its native form HA exists as a high molecular weight polymer, but during inflammation lower molecular weight fragments accumulate. We have identified a collection of inflammatory genes induced in macrophages by HA fragments but not by high molecular weight HA. These include several members of the chemokine gene family: macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, cytokine responsive gene-2, monocyte chemoattractant protein-1, and regulated on activation, normal T cell expressed and secreted. HA fragments as small as hexamers are capable of inducing expression of these genes in a mouse alveolar macrophage cell line, and monoclonal antibody to the HA receptor CD44 completely blocks binding of fluorescein-labeled HA to these cells and significantly inhibits HA-induced gene expression. We also investigated the ability of HA fragments to induce chemokine gene expression in human alveolar macrophages from patients with idiopathic pulmonary fibrosis and found that interleukin-8 mRNA is markedly induced. These data support the hypothesis that HA fragments generated during inflammation induce the expression of macrophage genes which are important in the development and maintenance of the inflammatory response.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Clark RA, Wikner NE, Doherty DE, Norris DA. Cryptic chemotactic activity of fibronectin for human monocytes resides in the 120-kDa fibroblastic cell-binding fragment. J Biol Chem. 1988 Aug 25;263(24):12115–12123. [PubMed]
  • Laskin DL, Soltys RA, Berg RA, Riley DJ. Activation of alveolar macrophages by native and synthetic collagen-like polypeptides. Am J Respir Cell Mol Biol. 1994 Jan;10(1):58–64. [PubMed]
  • Laurent TC, Fraser JR. Hyaluronan. FASEB J. 1992 Apr;6(7):2397–2404. [PubMed]
  • Saari H. Oxygen derived free radicals and synovial fluid hyaluronate. Ann Rheum Dis. 1991 Jun;50(6):389–392. [PMC free article] [PubMed]
  • McNeil JD, Wiebkin OW, Betts WH, Cleland LG. Depolymerisation products of hyaluronic acid after exposure to oxygen-derived free radicals. Ann Rheum Dis. 1985 Nov;44(11):780–789. [PMC free article] [PubMed]
  • Sampson PM, Rochester CL, Freundlich B, Elias JA. Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase. J Clin Invest. 1992 Oct;90(4):1492–1503. [PMC free article] [PubMed]
  • Forrester JV, Balazs EA. Inhibition of phagocytosis by high molecular weight hyaluronate. Immunology. 1980 Jul;40(3):435–446. [PMC free article] [PubMed]
  • West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science. 1985 Jun 14;228(4705):1324–1326. [PubMed]
  • Oksala O, Salo T, Tammi R, Häkkinen L, Jalkanen M, Inki P, Larjava H. Expression of proteoglycans and hyaluronan during wound healing. J Histochem Cytochem. 1995 Feb;43(2):125–135. [PubMed]
  • Underhill CB, Nguyen HA, Shizari M, Culty M. CD44 positive macrophages take up hyaluronan during lung development. Dev Biol. 1993 Feb;155(2):324–336. [PubMed]
  • Bartolazzi A, Peach R, Aruffo A, Stamenkovic I. Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development. J Exp Med. 1994 Jul 1;180(1):53–66. [PMC free article] [PubMed]
  • Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. [PubMed]
  • Bourguignon LY, Lokeshwar VB, Chen X, Kerrick WG. Hyaluronic acid-induced lymphocyte signal transduction and HA receptor (GP85/CD44)-cytoskeleton interaction. J Immunol. 1993 Dec 15;151(12):6634–6644. [PubMed]
  • Hall CL, Wang C, Lange LA, Turley EA. Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity. J Cell Biol. 1994 Jul;126(2):575–588. [PMC free article] [PubMed]
  • Murakami S, Miyake K, Kincade PW, Hodes RJ. Functional role of CD44 (Pgp-1) on activated B cells. Immunol Res. 1991;10(1):15–27. [PubMed]
  • Noble PW, Lake FR, Henson PM, Riches DW. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. J Clin Invest. 1993 Jun;91(6):2368–2377. [PMC free article] [PubMed]
  • Bitterman PB, Adelberg S, Crystal RG. Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J Clin Invest. 1983 Nov;72(5):1801–1813. [PMC free article] [PubMed]
  • Carré PC, Mortenson RL, King TE, Jr, Noble PW, Sable CL, Riches DW. Increased expression of the interleukin-8 gene by alveolar macrophages in idiopathic pulmonary fibrosis. A potential mechanism for the recruitment and activation of neutrophils in lung fibrosis. J Clin Invest. 1991 Dec;88(6):1802–1810. [PMC free article] [PubMed]
  • Gauldie J, Jordana M, Cox G. Cytokines and pulmonary fibrosis. Thorax. 1993 Sep;48(9):931–935. [PMC free article] [PubMed]
  • Rom WN, Basset P, Fells GA, Nukiwa T, Trapnell BC, Crysal RG. Alveolar macrophages release an insulin-like growth factor I-type molecule. J Clin Invest. 1988 Nov;82(5):1685–1693. [PMC free article] [PubMed]
  • Yanni G, Whelan A, Feighery C, Bresnihan B. Synovial tissue macrophages and joint erosion in rheumatoid arthritis. Ann Rheum Dis. 1994 Jan;53(1):39–44. [PMC free article] [PubMed]
  • Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Strieter RM. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest. 1992 Sep;90(3):772–779. [PMC free article] [PubMed]
  • Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Strieter RM. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994 Mar;93(3):921–928. [PMC free article] [PubMed]
  • Smith RE, Strieter RM, Phan SH, Lukacs NW, Huffnagle GB, Wilke CA, Burdick MD, Lincoln P, Evanoff H, Kunkel SL. Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury. J Immunol. 1994 Nov 15;153(10):4704–4712. [PubMed]
  • Standiford TJ, Rolfe MW, Kunkel SL, Lynch JP, 3rd, Burdick MD, Gilbert AR, Orringer MB, Whyte RI, Strieter RM. Macrophage inflammatory protein-1 alpha expression in interstitial lung disease. J Immunol. 1993 Sep 1;151(5):2852–2863. [PubMed]
  • Zhang K, Gharaee-Kermani M, Jones ML, Warren JS, Phan SH. Lung monocyte chemoattractant protein-1 gene expression in bleomycin-induced pulmonary fibrosis. J Immunol. 1994 Nov 15;153(10):4733–4741. [PubMed]
  • Lake FR, Noble PW, Henson PM, Riches DW. Functional switching of macrophage responses to tumor necrosis factor-alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha. J Clin Invest. 1994 Apr;93(4):1661–1669. [PMC free article] [PubMed]
  • Ohmori Y, Hamilton TA. IFN-gamma selectively inhibits lipopolysaccharide-inducible JE/monocyte chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating activity gene expression in mouse peritoneal macrophages. J Immunol. 1994 Sep 1;153(5):2204–2212. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Mbawuike IN, Herscowitz HB. MH-S, a murine alveolar macrophage cell line: morphological, cytochemical, and functional characteristics. J Leukoc Biol. 1989 Aug;46(2):119–127. [PubMed]
  • Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer. 1980 Aug;26(2):171–176. [PubMed]
  • Miyake K, Medina KL, Hayashi S, Ono S, Hamaoka T, Kincade PW. Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures. J Exp Med. 1990 Feb 1;171(2):477–488. [PMC free article] [PubMed]
  • Turley E, Moore D. Hyaluronate binding proteins also bind to fibronectin, laminin and collagen. Biochem Biophys Res Commun. 1984 Jun 29;121(3):808–814. [PubMed]
  • Rollins BJ, Stier P, Ernst T, Wong GG. The human homolog of the JE gene encodes a monocyte secretory protein. Mol Cell Biol. 1989 Nov;9(11):4687–4695. [PMC free article] [PubMed]
  • Lee TH, Lee GW, Ziff EB, Vilcek J. Isolation and characterization of eight tumor necrosis factor-induced gene sequences from human fibroblasts. Mol Cell Biol. 1990 May;10(5):1982–1988. [PMC free article] [PubMed]
  • Knudson W, Knudson CB. Assembly of a chondrocyte-like pericellular matrix on non-chondrogenic cells. Role of the cell surface hyaluronan receptors in the assembly of a pericellular matrix. J Cell Sci. 1991 Jun;99(Pt 2):227–235. [PubMed]
  • Kubo K, Nakamura T, Takagaki K, Yoshida Y, Endo M. Depolymerization of hyaluronan by sonication. Glycoconj J. 1993 Dec;10(6):435–439. [PubMed]
  • Lee HG, Cowman MK. An agarose gel electrophoretic method for analysis of hyaluronan molecular weight distribution. Anal Biochem. 1994 Jun;219(2):278–287. [PubMed]
  • de Belder AN, Wik KO. Preparation and properties of fluorescein-labelled hyaluronate. Carbohydr Res. 1975 Nov;44(2):251–257. [PubMed]
  • Penno MB, August JT, Baylin SB, Mabry M, Linnoila RI, Lee VS, Croteau D, Yang XL, Rosada C. Expression of CD44 in human lung tumors. Cancer Res. 1994 Mar 1;54(5):1381–1387. [PubMed]
  • Belitsos PC, Hildreth JE, August JT. Homotypic cell aggregation induced by anti-CD44(Pgp-1) monoclonal antibodies and related to CD44(Pgp-1) expression. J Immunol. 1990 Mar 1;144(5):1661–1670. [PubMed]
  • Shin HS, Drysdale BE, Shin ML, Noble PW, Fisher SN, Paznekas WA. Definition of a lipopolysaccharide-responsive element in the 5'-flanking regions of MuRantes and crg-2. Mol Cell Biol. 1994 May;14(5):2914–2925. [PMC free article] [PubMed]
  • Eierman DF, Johnson CE, Haskill JS. Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates. J Immunol. 1989 Mar 15;142(6):1970–1976. [PubMed]
  • Yannariello-Brown J, Frost SJ, Weigel PH. Identification of the Ca(2+)-independent endocytic hyaluronan receptor in rat liver sinusoidal endothelial cells using a photoaffinity cross-linking reagent. J Biol Chem. 1992 Oct 5;267(28):20451–20456. [PubMed]
  • Kiemle-Kallee J, Kreipe H, Radzun HJ, Parwaresch MR, Auerswald U, Magnussen H, Barth J. Alveolar macrophages in idiopathic pulmonary fibrosis display a more monocyte-like immunophenotype and an increased release of free oxygen radicals. Eur Respir J. 1991 Apr;4(4):400–406. [PubMed]
  • Lynch JP, 3rd, Standiford TJ, Rolfe MW, Kunkel SL, Strieter RM. Neutrophilic alveolitis in idiopathic pulmonary fibrosis. The role of interleukin-8. Am Rev Respir Dis. 1992 Jun;145(6):1433–1439. [PubMed]
  • Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, Cripps V, Austen L, Nance DM, Turley EA. Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol. 1992 Jun;117(6):1343–1350. [PMC free article] [PubMed]
  • Savani RC, Wang C, Yang B, Zhang S, Kinsella MG, Wight TN, Stern R, Nance DM, Turley EA. Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM. J Clin Invest. 1995 Mar;95(3):1158–1168. [PMC free article] [PubMed]
  • McCourt PA, Ek B, Forsberg N, Gustafson S. Intercellular adhesion molecule-1 is a cell surface receptor for hyaluronan. J Biol Chem. 1994 Dec 2;269(48):30081–30084. [PubMed]
  • Yurochko AD, Liu DY, Eierman D, Haskill S. Integrins as a primary signal transduction molecule regulating monocyte immediate-early gene induction. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9034–9038. [PMC free article] [PubMed]
  • Martin TR, Mongovin SM, Tobias PS, Mathison JC, Moriarty AM, Leturcq DJ, Ulevitch RJ. The CD14 differentiation antigen mediates the development of endotoxin responsiveness during differentiation of mononuclear phagocytes. J Leukoc Biol. 1994 Jul;56(1):1–9. [PubMed]
  • Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. [PubMed]
  • Jones PL, Schmidhauser C, Bissell MJ. Regulation of gene expression and cell function by extracellular matrix. Crit Rev Eukaryot Gene Expr. 1993;3(2):137–154. [PubMed]
  • Juliano RL, Haskill S. Signal transduction from the extracellular matrix. J Cell Biol. 1993 Feb;120(3):577–585. [PMC free article] [PubMed]
  • Wrenshall LE, Carlson A, Cerra FB, Platt JL. Modulation of cytolytic T cell responses by heparan sulfate. Transplantation. 1994 Apr 15;57(7):1087–1094. [PubMed]
  • Nettelbladt O, Bergh J, Schenholm M, Tengblad A, Hällgren R. Accumulation of hyaluronic acid in the alveolar interstitial tissue in bleomycin-induced alveolitis. Am Rev Respir Dis. 1989 Mar;139(3):759–762. [PubMed]
  • Nettelbladt O, Hällgren R. Hyaluronan (hyaluronic acid) in bronchoalveolar lavage fluid during the development of bleomycin-induced alveolitis in the rat. Am Rev Respir Dis. 1989 Oct;140(4):1028–1032. [PubMed]
  • McCord JM. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science. 1974 Aug 9;185(4150):529–531. [PubMed]
  • Papakonstantinou E, Karakiulakis G, Roth M, Block LH. Platelet-derived growth factor stimulates the secretion of hyaluronic acid by proliferating human vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9881–9885. [PMC free article] [PubMed]
  • Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed]
  • Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med. 1995 Jul 1;182(1):155–162. [PMC free article] [PubMed]
  • Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992 Dec 11;258(5089):1798–1801. [PubMed]
  • Bjermer L, Lundgren R, Hällgren R. Hyaluronan and type III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. Thorax. 1989 Feb;44(2):126–131. [PMC free article] [PubMed]

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