RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

The Ron receptor tyrosine kinase (TK) plays a regulatory role in the inflammatory response to acute lung injury induced by intranasal administration of bacterial LPS. Previously, we have shown that mice with a targeted deletion of the TK signaling domain of the Ron receptor exhibited more severe lung injury in response to intranasal LPS administration as evidenced by an increased leakage of albumin in the lungs and a greater thickening of the alveolar septa compared with wild-type mice. In addition, lung injury in the Ron TK-deficient (TK-/-) mice was associated with increased activation of the transcription factor, nuclear factor-kappa B (NF-kappa B), and significantly increased intrapulmonary expression of TNF alpha. TNF alpha, a multifunctional proinflammatory cytokine, is a central mediator in several disease states, including rheumatoid arthritis and sepsis. On the basis of the observation that TNF alpha production is increased in the Ron TK-/- mice and that macrophages are a major source of this cytokine, we hypothesized that the alterations observed in the Ron TK-/- mice may be due, in part, to Ron signaling, specifically in alveolar macrophages. To test this hypothesis, we used the wild-type and Ron TK-/- primary alveolar macrophages and the murine alveolar macrophage cell line, MH-S, to examine the effects of Ron activation on LPS-induced TNF alpha production and NF-kappa B activity. Here, we reported that Ron is expressed on alveolar macrophages and MH-S cells. Activation of Ron by its ligand, hepatocyte growth factor-like protein, decreases TNF alpha production in alveolar macrophages after LPS challenge. Decreased TNFa is associated with hepatocyte growth factor-like protein-induced decreases in NF-kappa B activation and increases in the NF-kappa B inhibitory protein, I kappa B. We also provided the first evidence for Ron as a negative regulator of Adam17, the metalloprotease involved in TNF alpha processing. These results indicate that Ron plays a critical role in regulation of alveolar macrophage signaling and validates this receptor as a target in TNF alpha-mediated pulmonary pathologies.