Effects of noninhibitory alpha-1-antitrypsin on primary human monocyte activation in vitro

A major function of alpha -1-antitrypsin (AAT) is the inhibition of overexp ressed serine proteinases during inflammation. However, it is also known th at the biological activity of AAT is affected by chemical modifications, in cluding oxidation of the reactive-site methionine, polymerization, and clea vage by unspecific proteases, all of which will result in AAT inactivation and/or degradation. All inactive forms of AAT can be detected in tissues an d fluids recovered from inflammatory sites. To test for a possible link bet ween the inflammation-generated, noninhibitory, cleaved form of AAT and cel lular processes associated with inflammation, we studied the effects of thi s form at varying concentrations on human monocytes in culture. We found th at cleaved AAT at concentrations ranging between 1 and 10 muM in monocyte c ultures over 24 h induces elevation in monocyte chemoattractant protein-1 ( MCP-1) and pro-inflammatory cytokines such as TNF alpha and IL-6 and also i ncreases production of interstitial collagenase (MMP-1) and gelatinase B (M MP-9), members of two different classes of matrix metalloproteinase. Moreov er, monocytes stimulated with higher doses of cleaved AAT show an increase in cellular oxygen consumption by about 30%, while native AAT under the sam e experimental conditions inhibits oxygen consumption by about 50%. These r esults indicate that the cleaved form of AAT may play a role in monocyte re cruitment and pro-inflammatory activation during inflammatory processes, an d also suggest that changes in structure occurring upon AAT cleavage could alter its functional properties with potential pathological consequences. ( C) 2001 Academic Press.