Regulation of Macrophage TNFα, IL-1β, and Ia (I-Aα) mRNA Expression during Peritonitis Is Site Dependent

Abstract

Failure of the immune system to successfully prevent organ failure after injury or infection may be associated with a shift in macrophage function from antigen recognition and presentation to overexpression of inflammatory cytokines. Regulation may be due to changes in macrophage gene expression. Levels of mRNA for tumor necrosis factor α (TNFα), interleukin-1 β (1L-1β), and the Ia subunit, I-Aα, in peritoneal macrophages, liver, spleen, kidney, and lung were measured following cecal ligation and puncture (CLP) in Swiss Webster mice. Northern blot analysis was performed using 32P-labeled mouse cDNA probes. Peritoneal macrophage TNFα and IL-1β mRNA expression increased 2.5- and 2-fold, respectively, by 6 hr after CLP and remained elevated at 24 hr. Peritoneal macrophage I-Aα mRNA levels decreased 8-fold by 24 hr after CLP. I-Aα mRNA expression in liver, spleen, kidney, and lung decreased following CLP, with a return toward normal levels by 8 days in all tissues except spleen. IL-1β and TNFα mRNA were barely detectable in liver and kidney. IL-1β mRNA tended to increase over time in lung and spleen, whereas TNFα mRNA in these tissues did not vary greatly after CLP. Muramyl dipeptide or monophosphoryl lipid A pretreatment of animals prior to CLP was ineffective in altering the expression of TNFα and I-Aα mRNA. We conclude that peritonitis is associated with an early increase in peritoneal macrophage TNFα and IL-1β mRNA levels and a sharp decline in macrophage I-Aα mRNA. Changes were less marked in tissues more remote from the infection. These results suggest that regulation of TNFα, IL-1β, and I-Aα expression during peritonitis occurs, at least in part, at the level of mRNA expression with dependence on proximity to the site of infection.