ALTERATIONS IN TUMOR NECROSIS FACTOR-α EXPRESSION BY HEPATIC MACROPHAGES FOLLOWING ACUTE CHOLESTATIC LIVER INJURY

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Abstract
The liver is unique for its large resident macrophage (HMΦ) population as a potential source of immunoregulatory cytokines. The present study was designed to determine HMΦ function in a rat model of cholestasis (CBDL). Northern blot analysis of TNF-α mRNA showed a profound difference in the dose response to bacterial lipopolysaccharide (LPS) between sham and CBDL HMΦ. Sham HMΦ demonstrated an 8-fold difference in induction of TNF-α mRNA versus CBDL HMΦ. TNF-α secretion, determined by enzyme-linked immunosorbent assay, was significantly higher from LPS-activated sham HMΦ versus the same cells activated with Gram-positive bacterial peptidoglycan while CBDL HMΦ were more responsive to peptidoglycan than to LPS. These results demonstrate stimulus- and response-specific functional alterations in the HMΦ 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 HMΦ.

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