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

The activation of a macrophage(M)-dependent proinflammatory cascade following thermal injuryplays an important role in the development of immunosuppression andincreased susceptibility to subsequent sepsis in burn patients. Incontrast, although interleukin (IL)-10, an anti-inflammatory cytokinethat can downregulate M activity, has also been implicated inpostburn immune dysfunction, its role in the regulation of Mfunction postburn remains unclear. To study this, C57BL/6 female micewere subjected to a 25% total body surface area third-degree scaldburn, and splenic Ms were isolated 7 days later. Lipopolysaccharide(LPS)-stimulated IL-10, IL-6, tumor necrosis factor (TNF)-, andnitric oxide (NO) production were significantly increased in the burngroup compared with shams. Blockade of endogenous IL-10 activityenhanced IL-6 and TNF- release, but not NO release, in both groups.The addition of exogenous IL-10 to the M cultures dose dependentlysuppressed production of these inflammatory mediators in both groups.The timing of IL-10 addition to the cultures in relation to LPSstimulation, however, was critical. The suppressive effect of exogenousIL-10 was attenuated in both groups when the cells were exposed toIL-10 at 4-6 h after LPS stimulation; however, Ms from injuredmice were significantly better able to maintain inflammatorymediator-productive capacity. The resistance of Ms from injured miceto IL-10-mediated suppression correlated with decreased IL-10 receptor(IL-10R) expression and increased CD11b expression. These findingssuggest that Ms, following thermal injury, display resistance tosuppression by IL-10 due in part to downregulation of IL-10R expression.