FcgammaR receptors activate MAP kinase and up-regulate the cyclooxygenase pathway without increasing arachidonic acid release in monocytic cells.

Abstract

THP-1 monocytic cells were stimulated with IgG-ovalbumin equivalence immune complexes (IC) and mAb reacting with both FcgammaRI and FcgammaRIIA. All of these stimuli were capable of activating the cells; however, different patterns of response were observed as regards activation of the p42-MAP/ERK kinase, triggering of the NF-kappaB/Rel system, production of chemotactic cytokines, and induction of the expression of cyclooxygenase-2 (COX-2). Activation of p42-MAP/ERK kinase was a constant finding, which occurred regardless of the type of stimulus applied, for instance, homotypic stimulation of a single type of receptor by cross-linking with specific mAb or heterotypic stimulation with both types of antibodies and IC. However, the activation of the MAP/ERK kinase cascade was not connected to the triggering of cytosolic phospholipase A(2) (cPLA(2)) and arachidonic acid (AA) release. The heterotypic stimulation of FcgammaR induced the expression of COX-2 in a time and dose-dependent manner and activated the NF-kappaB system as judged from the degradation of IkappaB-alpha protein. In summary, the present data indicate that activation of the p42-MAP/ERK pathway occurs after cross-linking FcgammaRI and FcgammaRIIA receptors in monocytic cells; however, this is not coupled to the cPLA(2) route, which leads to the release of AA. Noteworthy,heterotypic activation involving combined cross-linking of both FcgammaRI and FcgammaRIIA has a robust effect on the oxidative metabolism of AA by a mechanism involving kappaB-dependent trans-activation of COX-2.