Induction of cyclooxygenase-2 synthesis by ligation of the macrophage alpha 2-macroglobulin signalling receptor

We have studied the induction of cyclooxygenase-2 (COX-2) in macrophages co nsequent to ligating the alpha (2)-macroglobulin (alpha M-2) signalling rec eptor (alpha 2MSR) with receptor-recognized forms of alpha M-2 (alpha M-2*) . Macrophage stimulation with alpha M-2* increased total cellular and nucle ar COX-2 two- to threefold. The maximal increase in COX-2 occurred at a lig and concentration of 50-100 pM and after 2 h. Modulation of intracellular C a2+ levels or incubation of [S-35] methionine-labelled macrophages with act inomycin D, prior to treatment with alpha M-2*, markedly reduced the induct ion of total cellular and nuclear COX-2. Protein kinase C (PKC) or phosphol ipase A(2) (PLA(2)) inhibition in alpha M-2*-stimulated macrophages or inhi bition of the p21(ras)-dependent mitogen-activated protein kinase (MAPK) an d phosphoinositide 3-kinase (PI 3-kinase) signalling pathways also signific antly reduced alpha M-2*-induced total cellular and nuclear COX-2 expressio n. Thus, COX-2 induction is dependent on cPLA(2) activity, Ca2+ mobilizatio n, and PKC activity and requires participation of both the p21(ras)-depende nt MAPK and PI 3-kinase signalling pathways. COX-2 activation may mediate a lpha M-2*-induced mitogenesis, which we have previously observed in this an d other cell types. (C) 2001 Elsevier Science Inc. All rights reserved.