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,
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Nora Eccles Harrison Cardiovascular Research and Training Institute,
Eccles Program in Human Molecular Biology and Genetics, Salt Lake City, UT 84112; Departments of
Biochemistry,
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Internal Medicine,
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Pathology, and
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Pediatrics, University of Utah Health Sciences Center, Salt Lake City, UT 84112; and
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ICOS Corporation, Bothell, WA 98021
ICAM-3 is expressed at high levels on myeloid leukocytes, but its
function on these cells is unknown. We tested the hypothesis that it
transduces outside-in proinflammatory signals using immobilized mAbs to
engage ICAM-3 on freshly isolated human monocytes and neutrophils. Two
immobilized Abs that recognize epitopes in the extracellular domain 1
of ICAM-3, which is critical for recognition by the
L/ß2 integrin, potently induced
secretion of MIP-1, IL-8, and MCP-1 by monocytes and triggered IL-8
secretion by neutrophils. These chemokines are products of
immediate-early genes that are induced when myeloid cells are
activated. Chemokine secretion induced by "triggering" Abs was
greater than that induced by isotype-matched immobilized Abs against
ICAM-1, ICAM-2, PECAM-1, control Igs, or immobilized control proteins.
Coengagement of ICAM-3 and Fc receptors (Fc
RI or FcRII) was
required for maximal chemokine secretion by monocytes. Microscopy
documented that there is also dramatic spreading of monocytes when
surface ICAM-3 is engaged by immobilized Abs. Spreading was induced by
Fab and F(ab')2 fragments of triggering anti-ICAM-3
mAb, demonstrating direct outside-in signaling, but was not required
for chemokine secretion. These experiments indicate that ICAM-3 may
transmit outside-in signals when it is engaged by ß2
integrins during myeloid cell-cell interactions in inflammatory
lesions. Binding of Fc receptors by Ig in the local environment can
amplify the responses.
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