C1q-bearing immune complexes induce IL-8 secretion in human umbilical veinendothelial cells (HUVEC) through protein tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms: evidence that the 126 kD phagocytic C1q receptor mediates immune complex activation of HUVEC

Endothelial cells play a pivotal role in the initiation and perpetuation of inflammation. C1q, the first component of the classical pathway of complem ent, is a potent stimulus leading to endothelial cell activation and cytoki ne production. The specific cellular mechanisms through which endothelial c ells are stimulated by C1q are not known. We stimulated human umbilical vei n endothelial cells (HUVEC) with either monomeric C1q or C1q-bearing immune complexes (C1q-IC) in the presence or absence of inhibitors of protein tyr osine kinases (PTK) or mitogen-activated protein kinases (MAPK). C1q-IC, bu t not monomeric C1q, induced IL-8 production in dose- and time-dependent fa shion. R3, a cross-linking monoclonal IgM antibody against the126 kD phagoc ytic C1q receptor (C1qR), also stimulated IL-8 production. IL-8 mRNA accumu lation was detected by Northern blot analysis within 2 h of stimulation by the immune complexes and was enhanced by the addition of cycloheximide. Sec retion of IL-8 by C1q-IC stimulated HUVEC was completely blocked by the PTK inhibitor, genistein or the MAPK inhibitor, UO126. These experiments demon strate that C1q-IC-induced production of IL-8 in HUVEC is dependent upon th e activation of PTK and MAPK. These findings also support a role for the ph agocytic C1qR as an important activator of HUVEC by immune complexes.