Alterations in tumor necrosis factor-alpha expression by hepatic macrophages following acute cholestatic liver injury

The liver is unique for its large resident macrophage (HM Phi) population as a potential source of immunoregulatory cytokines. The present study was designed to determine HM Phi, function in a rat model of cholestasis (CBDL). Northern blot analysis of TNF-alpha mRNA showed a profound difference in the dose response to bacterial lipopolysaccharide (LPS) between sham and CBDL HM Phi. Sham HM Phi, demonstrated an 8-fold difference in induction of TNF-alpha mRNA versus CBDL HM Phi. TNF-alpha secretion, determined by enzyme-linked immunosorbent assay, was significantly higher from LPS-activated sham HM Phi versus the same cells activated with Gram-positive bacterial peptidoglycan while CBDL HM Phi were more responsive to peptidoglycan than to LPS. These results demonstrate stimulus- and response-specific functional alterations in the HM Phi population during acute cholestatic injury. We speculate that these functional alterations are phenotypically induced in acute liver injury resulting in responses that are not characteristic of normal HM Phi.