Initiation and progression of acute phase response to tissue injury and infection are controlled by members of the interleukin-6 (IL-6) type cytokines. Whereas IL-6 mediates systemic responses, oncostatin M (OSM) and leukemia inhibitory factor (LIF) act as critical mediators of local activation processes. OSM induces the expression of IL-6 and extracellular matrix proteins in fibroblast/stromal cells, whereas at sites of neuronal and muscle damage, LIF promotes regeneration. All IL-6- type cytokines induce components of the acute phase reaction in liver, however, hepatic and fibroblastic cells respond to IL-6, OSM and LIF by differential patterns of gene regulation and growth. By testing the hypothesis that cytokine-specific action is determined by the cytoplasmic domains of the subunits constituting the individual receptor complexes, we have assigned subunit-specific signaling functions to OSM receptor beta and LIF receptor alpha that are distinct from that of the common signal transducing subunit gp130. Since the precise mechanisms by which OSM- and LIF-specific responses are established are unknown, the goal of Aim 1 of this project is to identify functional motifs within the cytoplasmic domains of the OSMRbeta and LIFRalpha that determine specific responses in hepatic and fibroblastic cell models.
The second aim of this proposal is to understand how the cell integrates the signals of multiple cytokines and growth factors that cooperate with 1L- 6-type cytokines in mediating differential and cell type specific reduction in LIF and OSM responsiveness. Our work has suggested a preferential attenuation of the LIFR functions by a novel mechanism of LIFRalpha degradation that, in part, depends on a serine kinase motif in the cytoplasmic domain of LIFRalpha. The biochemical processes of LIFRalpha and OSMRbeta turnover and the pathways activated by insulin and growth factor trigger LIFRalpha degradation in trans will be defined in the hepatic and fibroblastic cell models. Understanding the cell type-specific regulation of IL-6-type cytokine receptor activities will assist in designing treatments that will manipulate beneficial IL-6 cytokine effects during inflammation and tissue repair.
Showing the most recent 10 out of 23 publications
