DIFFERENTIAL ROLES OF EXTRACELLULAR SIGNAL-REGULATED KINASE-1 2 AND P38(MAPK) IN INTERLEUKIN-1-BETA-INDUCED AND TUMOR NECROSIS FACTOR-ALPHA-INDUCED LOW-DENSITY-LIPOPROTEIN RECEPTOR EXPRESSION IN HEPG2 CELLS/

The inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor ne crosis factor-alpha (TNF), elevated in inflammatory, malignant, and in fectious diseases, induce low density lipoprotein (LDL) receptor trans cription in HepG2 cells, and such are induction can account for hypoch olesterolemia associated with these states. However, the signaling mec hanisms of cytokine-mediated LDL receptor induction are largely unexpl ored, In the present studies, we examined the potential involvement of different mitogen-activated protein kinase (MAPK) pathways. Northern analysis demonstrated that IL-1 beta or TNF significantly increased LD L receptor transcript in HepG2 cells, whereas expression of another ti ghtly regulated sterol-responsive squalene synthase gene was unaffecte d. IL-1 beta tread;ment resulted in transient activation of three MAPK cascades, namely p46/54(JNK), p38(MAPK), and ERK-1/2, with maximal ac tivation of 20-, 25-, and 3-fold, respectively, occurring 15-30 min af ter cytokine addition. PD98059, a specific inhibitor of MAPK kinase ac tivity, inhibited IL-lp-induced LDL receptor expression In contrast, S B202190, a specific inhibitor of p38(MAPK), enhanced IL-1 beta-induced LDL receptor expression, with a concomitant increase in ERK-1/2 activ ity. Similarly, TNF induced LDL receptor expression also required ERK- 1/2 activation. Finally, sterols repressed IL-1 beta induced receptor expression, without affecting ERK-1/2 activation. These results show t hat IL-IP-or TNF-induced LDL receptor expression requires ERK-1/2 acti vation, that the p38(MAPK) pathway negatively regulates LDL receptor e xpression, and that sterols inhibit induction at a point downstream of ERK-1/2 in HepG2 cells.