Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses
Susan E. Waltz, … , Klaus H. Kaestner, Sandra J.F. Degen
Susan E. Waltz, … , Klaus H. Kaestner, Sandra J.F. Degen
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):567-576. https://doi.org/10.1172/JCI11881.
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Article

Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses

Abstract

Ron receptor activation induces numerous cellular responses in vitro, including proliferation, dissociation, and migration. Ron is thought to be involved in blood cell development in vivo, as well as in many aspects of the immune response including macrophage activation, antigen presentation, and nitric oxide regulation. In previous studies to determine the function of Ron in vivo, mice were generated with a targeted deletion of the extracellular and transmembrane regions of this gene. Mice homologous for this deletion appear to die early during embryonic development. To ascertain the in vivo function of Ron in more detail, we have generated mice with a germline ablation of the tyrosine kinase domain. Strikingly, our studies indicate that this domain of Ron, and therefore Ron cytoplasmic signaling, is not essential for embryonic development. While mice deficient in this domain are overtly normal, mice lacking Ron signaling have an altered ability to regulate nitric oxide levels and, in addition, have enhanced tissue damage following acute and cell-mediated inflammatory responses.

Authors

Susan E. Waltz, Laura Eaton, Kenya Toney-Earley, Karla A. Hess, Belinda E. Peace, Jeffrey R. Ihlendorf, Ming-Hai Wang, Klaus H. Kaestner, Sandra J.F. Degen

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Evaluation of macrophage activation, NO production, and LPS-induced endo...
Evaluation of macrophage activation, NO production, and LPS-induced endotoxemia. Peritoneal macrophages were isolated from control (Ron TK+/+) and experimental (Ron TK–/–) mice. (a) The macrophages were incubated with control conditioned media (–HGFL, filled bars) or conditioned media containing recombinant HGFL (+HGFL, open bars). After 3 hours, the average percentage of activated macrophages were scored. Values represent the averages of three independent experiments performed in triplicate. (b) Peritoneal macrophages were isolated from control (filled bars) and experimental (open bars) mice. The macrophages were plated in the presence of conditioned media, conditioned media plus LPS and INF-γ, or conditioned media plus LPS, INF-γ, and HGFL. Nitrite levels in the supernatants of cell cultures were measured and normalized to levels found in macrophages cultured in conditioned media. Experiments were performed in triplicate with SE values indicated. (c) Loss of the TK domain of Ron results in an increased susceptibility to LPS-induced endotoxic shock. Cumulative survival data are shown for control (dotted lines) and experimental (solid lines) mice.