The cleaved form of the IL-6R binds secreted IL-6 and enhances its pleiotropic activity through the activation of cells that lack expression of IL-6R via trans-signaling through the ubiquitously expressed glycoprotein 130. In vitro studies have implicated ADAM17 in IL-6R shedding, yet the biological relevance of ADAM17 in this process has not been Cefcapene Pivoxil Hydrochloride inhibitor directly investigated in vivo. Our results reveal that in the context of lung inflammation, ADAM17 participates in the shedding of IL-6R, but in contrast to TNF-a and L-selectin, ADAM17 is not the primary sheddase of leukocyte IL-6R. ADAM10 has also been reported to cleave the IL-6R, and thus it will be interesting to directly investigate its role in IL-6R shedding in a setting of acute lung inflammation. It is well recognized that TNF-a induces an extensive array of Omnitarg downstream events that further promote inflammation, and thus the greatly diminished production of soluble TNF-a by ADAM17- deficient leukocytes likely contributed to the reduced levels of alveolar neutrophils as lung inflammation progressed after LPS exposure. For instance, TNF-a signaling has been directly shown to induce the production of neutrophil-tropic chemokines in the alveoli following LPS exposure. As CXCL1, CXCL2, and CXCL5 are major chemokines directing neutrophil recruitment into the murine lung, we examined their levels in the alveolar compartment of the lung in ADAM17-null and control mice. CXCL2 levels were found to be similar in the two groups of mice. However, CXCL5 and CXCL1 levels in ADAM17-null mice were significantly decreased at 2 hours and 8 hours, respectively, following LPS instillation. CXCL5 is primarily expressed by activated alveolar type II cells, and attenuated early production of soluble TNF-a by resident and recruited leukocytes in ADAM17-null mice may have delayed the activation of these cells and the initial production of CXCL5 in the airspace. CXCL1 is secreted by a variety of cells including neutrophils, and the time frame of its reduction in alveolar levels in ADAM17-null mice corresponded with the marked reduction in alveolar neutrophil numbers as inflammation progressed following LPS exposure.