INTERLEUKIN 10 SUPPRESSION OF MONOCYTE PROSTAGLANDIN-H SYNTHASE-2 - MECHANISM OF INHIBITION OF PROSTAGLANDIN-DEPENDENT MATRIX METALLOPROTEINASE PRODUCTION

Monocytes/macrophages are associated with chronic inflammatory lesions , such as periodontal disease and rheumatoid arthritis, in which there is extensive connective tissue destruction. Stimulation of human mono cytes results in the production of matrix metalloproteinases (MMPs) vi a a prostaglandin E(2) (PGE(2))-cAMP-dependent pathway. Modulation of many monocyte functions by interleukin 10 (IL-10) suggested that this cytokine may influence the signal transduction pathway leading to the production of MMPs by monocytes. Preincubation of monocytes with IL-10 for 1 h prior to stimulation with ConA resulted in significant inhibi tion of prostaglandin H synthase-2 (PGHS-2, the inducible form of pros taglandin synthase). In contrast, PGHS-1, the constitutive PGHS, was n ot affected by IL-10. Suppression of PGHS-2 mRNA and protein levels wa s detected at 1 ng/ml of IL-10 with maximal inhibition at 20 ng/ml Nuc lear run-on transcription assays performed on monocytes exposed to Con A or the combination of ConA and IL-10 indicated that IL-10 treatment suppressed PGHS-2 expression at the level of transcription. Attenuatio n of PGHS-2 by IL-10 was accompanied by decreased prostaglandin produc tion, including PGE(2). The decrease in prostaglandin production was p rimarily related to the effect of IL-10 on PGHS-2 since the release of arachidonic acid was unaffected by this cytokine. The inhibition of P GE(2) production by IL-10 resulted in the suppression of mRNA and prot ein for interstitial collagenase and 92-kDa type IV collagenase/ gelat inase (gelatinase B). This conclusion is supported by the ability of e xogenously added PGE(2) or dibutyryl cAMP to restore the production of MMPs in IL-10-treated monocytes. Additionally, PGHS-2 was also restor ed by PGE(2) or dibutyryl cAMP, indicating that PGHS-2 is regulated th rough a PGE(2)-cAMP amplification pathway. These data add further supp ort to the anti-inflammatory properties of IL-10.