Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44.
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.
McKee
C M
CM
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Penno
M B
MB
Cowman
M
M
Burdick
M D
MD
Strieter
R M
RM
Bao
C
C
Noble
P W
PW
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D015152:Blotting, Northern; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics; D054357:Chemokine CXCL10; D005786:Gene Expression Regulation / Q000276:immunology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D006820:Hyaluronic Acid / Q000276:immunology*; D007249:Inflammation / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D015846:Monokines / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D018960:Hyaluronan Receptors; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases