INDUCTION OF IL-12 AND CHEMOKINES BY HYALURONAN REQUIRES ADHESION-DEPENDENT PRIMING OF RESIDENT BUT NOT ELICITED MACROPHAGES

Components of the extracellular matrix (ECM) can regulate leukocyte ac tivation and function at inflammatory sites, Low molecular weight frag ments 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 prod uction by alveolar and bone-marrow derived macrophages. To determine t he cellular requirements for responsiveness to HA, we compared the eff ects of HMW-HA and LMW-HA on resident and thioglycollate-elicited muri ne peritoneal macrophages, We demonstrate that treatment of elicited m acrophages with LMW-HA, but not with HMW-HA, stimulated production of the chemokines RANTES and macrophage inflammatory protein-1 alpha and -1 beta, 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-C D44 mAb that blocks HA binding, In contrast to elicited macrophages, f reshly explanted resident peritoneal macrophages did not respond to LM W-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 th e potential importance of CD44/LMW-HA interactions in regulating the i mmune response at sites of inflammation and demonstrate that the state of differentiation of macrophages may determine their sensitivities t o matrix components.