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Immune Cell Interaction Unit, Mucosal Immunity Section, Laboratory for Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
We investigated the ability of chemoattractants to affect IL-12
production by human monocytes and dendritic cells. We found that
pretreatment of monocytes with macrophage chemoattractant proteins
(MCP-1 to -4), or C5a, but not stromal-derived factor-1, macrophage
inflammatory protein-1
, RANTES, or eotaxin, inhibited IL-12 p70
production in response to stimulation with Staphylococcus
aureus, Cowan strain 1 (SAC), and IFN-
. The production of
TNF-
and IL-10, however, was minimally affected by any of the
chemoattractants. The degree of inhibition of IL-12 p70 production by
MCP-1 to -4 was donor dependent and was affected by the autocrine
inhibitory effects of IL-10. In contrast, C5a profoundly suppressed
IL-12 production in an IL-10-independent fashion. Neither TGF-ß1 nor
PGE2 was important for the suppression of IL-12 by any of
the chemoattractants tested. The accumulation of mRNA for both IL-12
p35 and p40 genes was inhibited by chemokine pretreatment.
Interestingly, MCP-1 to -4 and C5a did not suppress IL-12 production by
monocyte-derived dendritic cells (DC) stimulated with CD40 ligand and
IFN-
or by SAC and IFN-
, suggesting that these factors may act at
the site of inflammation to suppress IL-12 and IFN-
production
rather than in the lymph node to affect T cell priming. Despite the
inability of C5a to inhibit IL-12 production by DCs, the receptor for
C5a (CD88) was expressed by these cells, and recombinant C5a induced a
Ca2+ flux. Taken together, these results define a range of
chemoattractant molecules with the ability to suppress IL-12 production
by human monocytes and have broad implications for the regulation of
immune responses in vivo.
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