title: Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages.
abstract: Components of the extracellular matrix (ECM) can regulate leukocyte activation and function at inflammatory sites. Low molecular weight fragments of the ECM glycosaminoglycan hyaluronan (LMW-HA) that accumulate in inflammation, but not the ubiquitous high molecular weight form of HA (HMW-HA), have been shown to induce cytokine and/or chemokine production by alveolar and bone-marrow derived macrophages. To determine the cellular requirements for responsiveness to HA, we compared the effects of HMW-HA and LMW-HA on resident and thioglycollate-elicited murine peritoneal macrophages. We demonstrate that treatment of elicited macrophages with LMW-HA, but not with HMW-HA, stimulated production of the chemokines RANTES and macrophage inflammatory protein-1alpha and -1beta. Further, we demonstrate that LMW-HA induced the production of biologically active IL-12, a proinflammatory cytokine not previously known to be regulated by cell-matrix interactions. The LMW-HA-induced production of IL-12 by elicited macrophages was inhibited by an anti-CD44 mAb that blocks HA binding. In contrast to elicited macrophages, freshly explanted resident peritoneal macrophages did not respond to LMW-HA. However, preculture in vitro before stimulation led to adhesion-dependent priming for LMW-HA-induced cytokine and chemokine production by resident macrophages. These results provide further evidence of the potential importance of CD44/LMW-HA interactions in regulating the immune response at sites of inflammation and demonstrate that the state of differentiation of macrophages may determine their sensitivities to matrix components.
authors.affiliation: Immunology Graduate Group, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hodge-Dufour
authors.forename: P W
authors.initials: PW
authors.lastname: Noble
authors.forename: M R
authors.initials: MR
authors.lastname: Horton
authors.forename: C
authors.initials: C
authors.lastname: Bao
authors.forename: M
authors.initials: M
authors.lastname: Wysoka
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: E
authors.initials: E
authors.lastname: Puré
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018960:Hyaluronan Receptors / Q000276:immunology / Q000502:physiology*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008970:Molecular Weight; D010537:Peritoneum / Q000166:cytology; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D013864:Thioglycolates / Q000633:toxicity
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D018960:Hyaluronan Receptors; D013864:Thioglycolates; D018664:Interleukin-12; D007371:Interferon-gamma; D006820:Hyaluronic Acid