Differential roles of extracellular signal-regulated kinase- 1/4 and p38(MAPK) in interleukin-1β- and tumor necrosis factor-α-induced low density lipoprotein receptor expression in HepG2 cells

Abstract

The inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF), elevated in inflammatory, malignant, and infectious diseases, induce low density lipoprotein (LDL) receptor transcription in HepG2 cells, and such an induction can account for hypocholesterolemia associated with these states. However, the signaling mechanisms of cytokine- mediated LDL receptor induction are largely unexplored. In the present studies, we examined the potential involvement of different mitogen-activated protein kinase (MAPK) pathways. Northern analysis demonstrated that IL-1β or TNF significantly increased LDL receptor transcript in HepG2 cells, whereas expression of another tightly regulated sterol-responsive squalene synthase gene was unaffected. IL-1β treatment resulted in transient activation of three MAPK cascades, namely p(46/54)(JNK), p38(MAPK), and ERK- 1/4 , with maximal activation of 20-, 25-, and 3-fold, respectively, occurring 15-30 min after cytokine addition. PD98059, a specific inhibitor of MAPK kinase activity, inhibited IL-1β-induced LDL receptor expression. In contrast, SB202190, a specific inhibitor of p38(MAPK), enhanced IL-1β-induced LDL receptor expression, with a concomitant increase in ERK- 1/4 activity. Similarly, TNF induced LDL receptor expression also required ERK- 1/4 activation. Finally, sterols repressed IL-1β induced receptor expression, without affecting ERK- 1/4 activation. These results show that IL-1β- or TNF- induced LDL receptor expression requires ERK- 1/4 activation, that the p38(MAPK) pathway negatively regulates LDL receptor expression, and that sterols inhibit induction at a point downstream of ERK- 1/4 in HepG2 cells.