Receptor subunit-specific action of oncostatin M in hepatic cells and its modulation by leukemia inhibitory factor

The related cytokines, interleukin-6 (IL-6), oncostatin M (OSM), and leukem ia inhibitory factor (LIF) direct the formation of specific heteromeric rec eptor complexes to achieve signaling. Each complex includes the common sign al-transducing subunit gp130. OSM and LIF also recruit the signaling compet ent, but structurally distinct OSMR beta and LIFR alpha subunits, respectiv ely. To test the hypothesis that the particularly prominent cell regulation by OSM is due to signals contributed by OSMR beta, we introduced stable ex pression of human or mouse OSMR beta in rat hepatoma cells which have endog enous receptors for IL-6 and LIF, but not OSM. Both mouse and human OSM eng aged gp130 with their respective OSMR beta subunits, but only human OSM als o acted through LIFR. Signaling by OSMR beta-containing receptors was chara cterized by highest activation of STATE and ERK, recruitment of the insulin receptor substrate and Jun-N-terminal kinase pathways, and induction of a characteristic pattern of acute phase proteins. Since LIF together with LIF R alpha appear to form a more stable complex with gp130 than OSM with gp130 and OSMR beta, co-activation of LIFR and OSMR resulted in a predominant LI F-like response. These results suggest that signaling by IL-6 cytokines is not identical, and that a hierarchical order of cytokine receptor action ex ists in which LIFR ranks as dominant member.