Members of the chemokine gene superfamily are known to play a central role in leukocyte extravasation; however, their involvement in acute inflammation in response to micro-organisms has not yet been well studied. We have therefore investigated the role of murine macrophage-inflammatory protein (muMIP) 1α and muMIP-2 in the inflammatory response mounted against the bacteria Salmonella enteritidis and the Sacchromyces cerevisiae cell wall component, zymosan. Leukocyte extravasation was monitored in murine s.c. air pouches. Both agonists induced accumulation of leukocytes in a dose- and time-dependent manner, with the response peaking after 4 h and declining thereafter. The inflammatory exudate comprised mainly neutrophils; however, an increase in eosinophil accumulation was also observed in response to zymosan. The production of both muMIP-1α and muMIP-2 increased with time in response to both the agonists, although production was more sustained in response to the bacteria. Prior treatment of mice with neutralizing Abs against muMIP-1α or muMIP-2, either alone or in combination, failed to attenuate the accumulation of leukocytes in response to the agonists. In contrast, the anti-muMIP-2 Abs significantly inhibited leukocyte recruitment in response to S. enteritidis in complement-deficient mice. Taken together, these data show that while muMIP-1α and muMIP-2 are produced in response to phagocytosis of micro-organisms in s.c. tissue, under these circumstances components of the complement pathway appear to play a dominant role in the recruitment of neutrophils.

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SUMMARY:Fractalkine (FKN/CX 3 CL1) is an atypical chemokine, for which a major biological function has not yet emerged.However, recent data suggest a role in immune responses in the skin. In this study, we analyzed fractalkine (FKN) secretion by human-dermal fibroblasts after exposure to pro-inflammatory cytokines or to invasive and noninvasive strains of Escherichia coli. Incubation of fibroblasts with TNF-␣ and IL-1␤ induced a delayed expression of soluble FKN, compared with the rapid secretion of other chemokines including IL-8 (CXCL8), monocyte chemotactic protein-1 (CCL2), and RANTES (regulated upon activation, normal T cell expressed and secreted; CCL5). TNF-␣ and IFN-␥ gamma were more potent at inducing FKN secretion than was IL-1␤. Very little FKN was detected on the cell surface. FKN was not detected after incubation with the bacteria, regardless of the strain used. In contrast, both invasive and noninvasive E. coli triggered the release of IL-8 and monocyte chemotactic protein-1 in a dose-response manner, whereas RANTES was produced only in response to the invasive strain. Finally, incubation of fibroblasts with the invasive strain of E. coli inhibited TNF-␣-and IFN-␥-induced production of FKN. These results demonstrate for the first time that human-dermal fibroblasts express FKN, and that the characteristics of FKN secretion are distinct from those of other chemokines produced by these cells during immune responses in the dermis. In addition, our data indicate that bacterial invasion of dermal fibroblasts actively modulates FKN expression. (Lab Invest 2003, 83:721-730).

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