Resistance of macrophages to the suppressive effect of interleukin-10 following thermal injury.
The activation of a macrophage (Mphi)-dependent proinflammatory cascade following thermal injury plays an important role in the development of immunosuppression and increased susceptibility to subsequent sepsis in burn patients. In contrast, although interleukin (IL)-10, an anti-inflammatory cytokine that can downregulate M phi activity, has also been implicated in postburn 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 Mphis were isolated 7 days later. Lipopolysaccharide (LPS)-stimulated IL-10, IL-6, tumor necrosis factor (TNF)-alpha, and nitric oxide (NO) production were significantly increased in the burn group compared with shams. Blockade of endogenous IL-10 activity enhanced IL-6 and TNF-alpha 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 groups. The timing of IL-10 addition to the cultures in relation to LPS stimulation, however, was critical. The suppressive effect of exogenous IL-10 was attenuated in both groups when the cells were exposed to IL-10 at 4-6 h after LPS stimulation; however, Mphis from injured mice were significantly better able to maintain inflammatory mediator-productive capacity. The resistance of Mphis from injured mice to IL-10-mediated suppression correlated with decreased IL-10 receptor (IL-10R) expression and increased CD11b expression. These findings suggest that Mphis, following thermal injury, display resistance to suppression by IL-10 due in part to downregulation of IL-10R expression.
Schwacha
M G
MG
Center for Surgical Research, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. Martin.Schwacha@ccc.uab.edu
Schneider
C P
CP
Bland
K I
KI
Chaudry
I H
IH
D000818:Animals; D002056:Burns / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism; D053701:Receptors, Interleukin-10; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide