Regulation of Macrophage IL-10 Production Postinjury via ??2 Integrin Signaling and the P38 MAP Kinase Pathway

Abstract

Although LPS receptor (CD14) signaling is mediated in part by β2 integrins, the role of β2 integrins in macrophage LPS signaling postinjury remains unknown. To study this, splenic macrophages were isolated from mice 7 days postburn, and inflammatory mediator production was determined. Macrophages isolated from injured mice produced higher levels of PGE2, TNF-α, IL-6, and IL-10 and lower levels of IL-12 in response to LPS stimulation than did cells from sham-treated mice. Blockade of β2 integrin signaling by addition of antibodies against the CD11b (αCD11b) to the cultures increased IL-10 production by macrophages from injured mice without affecting other mediators. In contrast, sham macrophage responses to LPS were unaffected by αCD11b. Inhibition of p38 MAP kinase activity attenuated IL-10 production and abrogated the enhanced IL-10 response induced by αCD11b, whereas ERK 1/2 inhibition had no effect. Burn injury was associated with increased levels of total and phosphorylated p38 MAP kinase. These findings indicate that LPS signaling via β2 integrins acts to attenuate the exaggerated induction of IL-10 by macrophages postinjury. Moreover, this effect of β2 integrin signaling postinjury appears to be downstream of the p38 MAP kinase pathway and is independent of other markers of macrophage hyperactivity.