COENGAGEMENT OF ICAM-3 AND FC-RECEPTORS INDUCES CHEMOKINE SECRETION AND SPREADING BY MYELOID LEUKOCYTES

ICAM-3 is expressed at high levels on myeloid leukocytes, but its func tion on these cells is unknown, We tested the hypothesis that it trans duces outside-in proinflammatory signals using immobilized mAbs to eng age ICAM-3 on freshly isolated human monocytes and neutrophils. Two im mobilized Abs that recognize epitopes in the extracellular domain 1 of ICAM-3, which is critical for recognition by the alpha(L)/beta(2) int egrin, potently induced secretion of MIP-1 alpha, IL-8, and MCP-1 by m onocytes and triggered IL-8 secretion by neutrophils. These chemokines are products of immediate-early genes that are induced when myeloid c ells are activated. Chemokine secretion induced by ''triggering'' Abs was greater than that induced by isotype-matched immobilized Abs again st ICAM-1, ICAM-2, PECAM-1, control Igs, or immobilized control protei ns, Coengagement of ICAM-3 and Fc receptors (Fc gamma RI or Fc gamma R II) was required for maximal chemokine secretion by monocytes, Microsc opy documented that there is also dramatic spreading of monocytes when surface ICAM-3 is engaged by immobilized Abs, Spreading was induced b y Fab and F(ab')(2) fragments of triggering anti-ICAM-3 mAb, demonstra ting direct outside-in signaling, but was not required for chemokine s ecretion. These experiments indicate that ICAM-3 may transmit outside- in signals when it is engaged by beta(2) integrins during myeloid cell -cell interactions in inflammatory lesions. Binding of Fc receptors by Ig in the local environment can amplify the responses.