The Ron receptor tyrosine kinase plays a regulatory role in the inflammatory response to acute lung injury induced by intranasal administration of bacterial lipopolysaccharide (LPS). Previously, we have showen that mice with a targeted deletion of the tyrosine kinase (TK) signaling domain of the Ron receptor exhibited more severe lung injury in response to intranasal LPS administration as evidenced by increased leakage of albumin in the lungs and a greater thickening of the alveolar septae compared to 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 kappaB (NF-κB) and significantly increased intrapulmonary expression of tumor necrosis factor alpha (TNFα). TNFα, a multifunctional pro-inflammatory cytokine, is a central mediator in several disease states including rheumatoid arthritis and sepsis. Based on the observation that TNFα 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 Ron TK−/− mice may be due, in part, to Ron signaling specifically in alveolar macrophages. To test this hypothesis, wild-type and Ron TK−/− primary alveolar macrophages and the murine alveolar macrophage cell line, MH-S, were used to examine the effects of Ron activation on LPS-induced TNFα production and NK-κB activity. Here, we report that Ron is expressed on alveolar macrophages and MH-S cells. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL), decreases TNFα production in alveolar macrophages following LPS challenge. Decreased TNFα is associated with HGFL-induced decreases in NF-κB activation and increases in the NF-κB inhibitory protein, IκB. We also provide the first evidence for Ron as a negative regulator of Adam17, the metalloprotease involved in TNFα processing. . These results indicate that Ron plays a critical role in regulation of alveolar macrophage signaling, and validates this receptor as a target in TNFα-mediated pulmonary pathologies.