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Cytokine Research Unit, School of Pathology, Faculty of Medicine, University of New South Wales, Sydney, Australia
The murine calcium binding protein S100A8 (A8) is a leukocyte
chemoattractant, but high levels may be protective and scavenge
hypochlorite. A8 is induced by LPS, IFN-
, and TNF in elicited
macrophages. Th2 cytokines generally suppress proinflammatory gene
expression, and IL-4 and IL-13 partially decreased A8 induction in
macrophages and endothelial cells stimulated by LPS or IFN. In
contrast, IL-10 synergized with LPS and IFN to increase mRNA levels
9-fold and secreted A8 levels 
4-fold. IL-10 decreased the optimal
time of mRNA expression induced by LPS from 24 to 8 h. Blocking
experiments indicated that endogenous IL-10 contributes to gene
induction by LPS. Cooperation between IL-10 and LPS was not due to
altered mRNA stability but was dependent on de novo protein synthesis.
Transfection analysis with A8 luciferase constructs confirmed that
synergy was due to increased transcription. The region of the promoter
involved was localized to a 178-bp fragment flanking the transcription
start site of the gene. This region was also responsible for the
suppressive effects of IL-4 and IL-13. Forskolin, CTP-cAMP, and
PGE2 also enhanced LPS- and IFN-induced A8 mRNA, whereas
indomethacin significantly reduced synergy between IL-10 and LPS.
Mitogen-activated protein kinase/cyclooxygenase 2/cAMP pathways
involving CCAAT-enhancing binding protein, located within the active
promoter, may mediate A8 gene up-regulation in a manner mechanistically
distinct to genes regulated by IL-10 via the STAT pathway. A8 exhibits
pleiotropic effects, and the high levels secreted as a result of IL-10
synergy may regulate untoward inflammatory damage by virtue of its an
antioxidant capacity.
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