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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Figure 5

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Enhanced irritant and allergic CD in mice lacking the TK domain of Ron. ...
Enhanced irritant and allergic CD in mice lacking the TK domain of Ron. For acute irritant CD, experimental (Ron TK–/–) and control (Ron TK+/+) mice were challenged with a phenol solution as described in Methods (a and b). (a) Representative histological sections of ears following vehicle (unchallenged) and phenol application (challenged). ×100 magnification. (b) The average thickness of the ears were calculated and expressed as a percentage of increase over the control ear for each animal. The scatter diagram shows the values for each animal along with mean values (line) for each group. Mice lacking the TK domain of Ron displayed a significantly greater amount of ear swelling (P < 0.01). (c and d) To induce allergic contact hypersensitivity, mice were sensitized and challenged with DNFB as described in Methods. (c) Representative histological sections of ears. (d) Ear measurements were taken and expressed as a percentage of increase over the control ear. The scatter diagram depicts values determined for each animal as well as the population mean (line). Deficiencies in the TK domain of Ron result in a significantly exaggerated contact hypersensitivity response (P < 0.01).