INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1, CD54) EXPRESSION IN HUMAN HEPATOCYTIC CELLS DEPENDS ON PROTEIN-KINASE-C

Background/Aims: intercellular adhesion molecule-1 has mainly been stu died in lymphoid, endothelial, and epithelial cells. Intercellular adh esion molecule-1 plays a central role in many immune responses, and we have previously studied its regulation in hepatocytes. Here we report how manipulation of intracellular signal systems influenced its expre ssion. Methods: The constitutive and cytokine-induced expression of in tercellular adhesion molecule-1 mRNA and protein was studied in the hu man hepatocytic cell lines Hep G2 and SK-Hep-1. Results: When agonists and antagonists of protein kinase C, calmodulin, and protein kinase A mere introduced in addition to prostaglandin E2 and a cyclooxygenase inhibitor only the protein kinase C activator phorbol 12-myristate 13- acetate resulted in a rapid and dose-dependent increase in intercellul ar adhesion molecule-1 protein and mRNA. Phorbol 12-myristate 13-aceta te stimulated sustained high levels of intercellular adhesion molecule -1 protein, whereas the corresponding mRNA response was biphasic, peak ing at 3 h. Actinomycin D blocked the stimulatory mRNA phase, suggesti ng that de novo transcription was induced. Coincubation with phorbol 1 2-myristate 13-acetate and the protein synthesis inhibitor cycloheximi de gave considerably higher mRNA levels than with phorbol 12-myristate 13-acetate alone. Protein kinase C may therefore even stimulate synth esis of proteins that speed up the turnover of intercellular adhesion molecule-1 mRNA. The protein kinase C inhibitor staurosporine abrogate d the induction of intercellular adhesion molecule-1 by phorbol 12-myr istate 13-acetate, indicating that this effect was indeed exerted by p rotein kinase C. More original was our observation that staurosporine also completely blocked the stimulatory effects of interferon-gamma, t umour necrosis factor-alpha, and interleukin-1. Recent reports have no ted that these cytokines apparently use receptors which activate diffe rent intracellular pathways. We also noted that the glucocorticoid dex amethasone partially inhibited the stimulation of intercellular adhesi on molecule-1 by these cytokines. This phenomenon could be important f or the immunosuppressive effects of corticosteroids in patients Frith liver disease.Conclusions: Our data suggest that a certain level of pr otein kinase C activity is mandatory for liver cells in cytokine-media ted upregulation of intercellular adhesion molecule-1.