EFFECT OF CHOLERA-TOXIN AND PERTUSSIS TOXIN ON PROSTAGLANDIN-H SYNTHASE-2, PROSTAGLANDIN E(2), AND MATRIX METALLOPROTEINASE PRODUCTION BY HUMAN MONOCYTES

Activation of human monocytes induces the production of matrix metallo proteinases (MMPs) through a prostaglandin E(2) (PGE(2))-cAMP-dependen t pathway. Since G-proteins have been documented to modulate adenylyl cyclase, we examined the effect of G-protein ADP-ribosylating agents, cholera toxin (CT) and pertussis toxin (PT), on the signal transductio n pathway that culminates in the production of monocyte MMPs. Although CT elevated cAMP levels in both unstimulated and concanavalin A (Con A)-stimulated monocytes, it enhanced the production of prostaglandin H synthase-2 (PGH synthase-2, PGHS-2) protein, prostaglandins, intersti tial collagenase, and 99-kDa type IV collagenase/gelatinase only in Co n A-stimulated monocytes. Additionally the indomethacin-mediated suppr ession of Con A-induced monocyte interstitial collagenase and 92-kDa t ype IV collagenase/gelatinase production could be reversed by CT. In c ontrast to the actions of CT, PT treatment suppressed the levels of cA MP, PGHS-2, PGE(2), interstitial and 92-kDa type IV collagenase/gelati nase in Con A-stimulated monocytes. The regulation of MMP production b y these toxins appears to be mediated primarily through their effect o n adenylyl cyclase since the release of arachidonic acid was relativel y unaffected by these agents. These findings provide evidence that G-p roteins may be involved in either the enhancement or suppression of th e eicosanoid-cAMP-dependent signal transduction pathway that results i n the production of monocyte MMPs. (C) 1994 Academic Press, Inc.