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) populat ion as a potential source of immunoregulatory cytokines. The present s tudy was designed to determine HM Phi, function in a rat model of chol estasis (CBDL). Northern blot analysis of TNF-alpha mRNA showed a prof ound 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-alp ha secretion, determined by enzyme-linked immunosorbent assay, was sig nificantly higher from LPS-activated sham HM Phi versus the same cells activated with Gram-positive bacterial peptidoglycan while CBDL HM Ph i were more responsive to peptidoglycan than to LPS. These results dem onstrate 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 H M Phi.