title: Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production.
abstract: 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 monocytes results in the production of matrix metalloproteinases (MMPs) via a prostaglandin E2 (PGE2)-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. Pre-incubation of monocytes with IL-10 for 1 h prior to stimulation with ConA resulted in significant inhibition of prostaglandin H synthase-2 (PGHS-2, the inducible form of prostaglandin synthase). In contrast, PGHS-1, the constitutive PGHS, was not affected by IL-10. Suppression of PGHS-2 mRNA and protein levels was detected at 1 ng/ml of IL-10 with maximal inhibition at 20 ng/ml. Nuclear run-on transcription assays performed on monocytes exposed to ConA or the combination of ConA and IL-10 indicated that IL-10 treatment suppressed PGHS-2 expression at the level of transcription. Attenuation of PGHS-2 by IL-10 was accompanied by decreased prostaglandin production, including PGE2. The decrease in prostaglandin production was primarily related to the effect of IL-10 on PGHS-2, since the release of arachidonic acid was unaffected by this cytokine. The inhibition of PGE2 production by IL-10 resulted in the suppression of mRNA and protein for interstitial collagenase and 92-kDa type IV collagenase/gelatinase (gelatinase B). This conclusion is supported by the ability of exogenously added PGE2 or dibutyryl cAMP to restore the production of MMPs in IL-10-treated monocytes. Additionally, PGHS-2 was also restored by PGE2 or dibutyryl cAMP, indicating that PGHS-2 is regulated through a PGE2-cAMP amplification pathway. These data add further support to the anti-inflammatory properties of IL-10.
authors.affiliation: Cellular Immunology Section, Laboratory of Immunology, NIDR, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: P M
authors.initials: PM
authors.lastname: Mertz
authors.forename: D L
authors.initials: DL
authors.lastname: DeWitt
authors.forename: W G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.forename: L M
authors.initials: LM
authors.lastname: Wahl
mesh_terms: D000595:Amino Acid Sequence; D016718:Arachidonic Acid / Q000378:metabolism; D003994:Bucladesine / Q000378:metabolism; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016861:Cyclooxygenase Inhibitors; D016753:Interleukin-10; D016718:Arachidonic Acid; D003994:Bucladesine; D011451:Prostaglandin-Endoperoxide Synthases; D017364:Collagenases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone