Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta production in primary human monocytes through a pathway dependent on nuclear factor-kappa B

Chemokines and adhesion molecules such as integrins play a major part in th e trafficking, extravasation, and recruitment of leukocytes to inflammatory sites. This study investigated the effects Of beta (2) integrin engagement on chemokine production by freshly isolated human monocytes. We found that ligation of CD11 b or CD11c but not CD11a alpha chains of beta (2) integri ns by antibodies or soluble CD23 (sCD23) fusion proteins rapidly induced tr anscription and secretion of interleukin 8, macrophage inflammatory protein (MIP) 1 alpha, and MIP-1 beta. Because the promoters of these chemokine ge nes contain kappaB binding sites, we assessed the possible role of nuclear factor-kappaB (NF-kappaB) in controlling induction of the genes through bet a (2) integrin engagement. Electrophoretic mobility shift assays showed tha t sCD23 or antibodies to CD11b or to CD11c upregulated DNA-binding activity of NF-kappaB. Activation of NF-kappaB was accompanied by degradation of it s cytosolic inhibitor I kappaB-alpha. Blockade of depletion of I kappaB-alp ha by proteasome inhibitors (proteasome inhibitor I or acetyl-leucinyl-leuc inyl-norleucinal) led to concomitant inhibition of NF-kappaB DNA-binding ac tivity and expression of MIP-1 alpha and MIP-1 beta messenger RNA induced b y beta (2) integrin ligation. These results suggest that triggering of CD11 b or CD11c beta (2) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF-kappaB and subsequent secre tion of MIP-1 alpha and MIP-1 beta that may have an important role in recru itment of other inflammatory cells during initiation of an inflammatory res ponse. (Blood. 2001;97:2932-2940) (C) 2001 by The American Society of Hemat ology.