Resistance of macrophages to the suppressive effect of interleukin-10 following thermal injury

The activation of a macrophage (M phi)-dependent proinflammatory cascade fo llowing thermal injury plays an important role in the development of immuno suppression and increased susceptibility to subsequent sepsis in burn patie nts. In contrast, although interleukin (IL)-10, an antiinflammatory cytokin e that can downregulate M phi activity, has also been implicated in postbur n immune dysfunction, its role in the regulation of M phi function postburn remains unclear. To study this, C57BL/6 female mice were subjected to a 25 % total body surface area third-degree scald burn, and splenic M phi s were isolated 7 days later. Lipopolysaccharide (LPS)-stimulated IL-10, IL-6, tu mor necrosis factor (TNF)-alpha, and nitric oxide (NO) production were sign ificantly increased in the burn group compared with shams. Blockade of endo genous IL-10 activity enhanced IL-6 and TNF-a release, but not NO release, in both groups. The addition of exogenous IL-10 to the M phi cultures dose dependently suppressed production of these inflammatory mediators in both g roups. The timing of IL-10 addition to the cultures in relation to LPS stim ulation, however, was critical. The suppressive effect of exogenous IL-10 w as attenuated in both groups when the cells were exposed to IL-10 at 4-6 h after LPS stimulation; however, M phis from injured mice were significantly better able to maintain inflammatory mediator-productive capacity. The res istance of M phis from injured mice to IL-10-mediated suppression correlate d with decreased IL-10 receptor (IL-10R) expression and increased CD11b exp ression. These findings suggest that M phis, following thermal injury, disp lay resistance to suppression by IL-10 due in part to downregulation of IL- 10R expression.