HYPERGLYCEMIC LEVELS OF GLUCOSE INHIBIT INTERLEUKIN-1 RELEASE FROM RAW-264.7 MURINE MACROPHAGES BY ACTIVATION OF PROTEIN-KINASE-C

Diabetic patients with hyperglycemia (high blood glucose) have frequen t and persistent bacterial infections linked to significantly diminish ed bactericidal activity and macrophage function, Interleukin-1 (IL-1) , released primarily from activated macrophages, is a key mediator of effective host defense against microorganisms. We observe that hypergl ycemic levels of D-glucose (8-20 mM) inhibit the release of IL-1 by li popolysaccharide-stimulated RAW 264.7 murine macrophage cells. An inhi bitor of glucose transport and metabolism, 2-deoxyglucose, prevents th is inhibition of IL-1 release, High levels (8-20 mM) of fructose and m annose (but not galactose or L-glucose) also inhibit the release of IL -1 activity, suggesting that metabolism is required for IL-1 inhibitio n. Immunoprecipitation and activity measurements demonstrate that high glucose levels block the release of IL-1 but do not inhibit IL-1 prod uction, High glucose levels (20 mM) increase protein kinase C (PKC) ac tivity, and inhibitors of PKC block the inhibitory effects of glucose. Phorbol 12-myristate 13-acetate, an agonist of PKC, mimics glucose-in duced inhibition of IL-1 release. These results demonstrate that high glucose levels inhibit IL-1 release (but not production) by RAW 264.7 murine macrophages, and this inhibition is mediated by PKC activation. These studies suggest that persistent infections in hyperglycemic pat ients may be due to an inhibition of IL-1 release from macrophages.