THE IMMUNOGLOBULIN-LIKE MODULE OF GP130 IS REQUIRED FOR SIGNALING BY INTERLEUKIN-6, BUT NOT BY LEUKEMIA INHIBITORY FACTOR

The transmembrane protein gp130 is a shared component of the receptor complexes for the interleukin-6 (IL-6)-type cytokines, which include I L-6, leukemia inhibitory factor (LIF) and oncostatin M (OSM). In addit ion to its role in the generation of high affinity receptors, gp130 is required for signal transduction by these cytokines. In the present s tudy we have examined the role of the N-terminal located, extracellula r immunoglobulin (Ig)-like module of gp130 in signal transduction by I L-6 and LIF. We have expressed wild-type human gp130 or three mutants in murine myeloid M1-UR21 cells that lack functional endogenous gp130 but express the IL-6 receptor (IL-GR) and the LIF receptor (LIFR). By measuring cellular responses, such as morphological changes upon diffe rentiation, soft agar colony formation, and induction of tyrosine phos phorylation of the signal transducer and activator of transcription, S TAT3, we show that signaling by IL-6, but not LIF, is significantly re duced by mutations in the Ig-like module of gp130. However, the bindin g of I-125-labeled IL-6 or LIF is not affected by these mutations. We also present evidence that the Ig-like module forms part of the epitop e of an anti-gp130 monoclonal antibody that neutralizes the bioactivit y of IL-6, but not of LIF or OSM. The data suggest that gp130-activati on by IL-6 and LIF requires different regions of gp130, that the Ig-li ke module of gp130 may be required for IL B-induced gp130 dimerization , and that the stoichiometry of the high affinity IL-6 receptor-comple x differs from those of the receptor-complexes for LIF and OSM.