CYTOKINES ONCOSTATIN-M AND INTERLEUKIN-1 REGULATE THE EXPRESSION OF THE IL-6 RECEPTOR (GP80,GP130)

The steady-state mRNA levels of the interleukin 6 receptor (IL-6R, gp80) and its signal transducing molecule, gp130, were examined in the rat hepatoma cell line, H-35, stimulated by cytokines IL-6, IL-1, oncostatin RI (OSM) and/or Dexamethasone (Dex). In contrast to our previous findings in vivo [Geisterfer ef al., 1993, Cytokine, 5:1] in vitro Dex seemed to be the major stimulator of IL-6R mRNA expression, whereas IL-6 seemed to have little effect on the expression of its own receptor mRNA levels. However, the presence of other cytokines influenced the Hex mediated stimulation of IL-6R expression. OSM stimulated IL-6R mRNA levels. At 6 h, cells stimulated with OSM showed a 2.1-fold increase in IL-6R mRNA expression. This stimulation was additive with the Hex-mediated stimulation of IL-6R mRNA levels. In contrast, IL-1 inhibited the Dex-mediated stimulation of IL-6R mRNA. At the same time, IL-1 stimulated the presence of a second smaller mRNA transcript. This mRNA species contained the extracellular domain but lacked both the transmembrane and cytoplasmic domains of the IL-6R, suggesting alternate splicing, possibly coding for a soluble form of gp80. Unlike the gp80 IL-6R molecule, the expression of the gp130 molecule normally expressed as two species of mRNA was not regulated to any major extent in vitro. IL-1 and OSM stimulated both mRNA bands (7.5 and 9.0 kb) approximately 2-fold, whereas IL-6 stimulated mainly the upper 9.0 kb mRNA band. Cysteine proteinase inhibitor (CPI), mRNA and protein levels were elevated by combinations of cytokines; however, IL-1 seemed to inhibit the IL-6 + Dex mediated stimulation of CPI mRNA, possibly through inhibition of IL-6R expression and induction of a soluble form of the receptor. This study showed that both IL-1 and OSM are involved in the regulation of the IL-6 receptor complex, and that different combinations of cytokines can affect the complexity and magnitude of the hepatic acute phase response. (C) 1995 Academic Press Limited.