Modulation of TNF-alpha-mediated acute lung inflammation: A role for IL-1beta and soluble TNF receptors

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are key mediators of numerous lung inflammatory diseases. Induced by similar stimuli, in many cell types IL-1beta modifies expression and solubilization of the two TNF receptors, TNFR1 and TNFR2. These proteins are cleaved from the cell surface primarily by the metalloprotease TNF-alpha converting enzyme (TACE) generating soluble forms still capable of binding TNF-alpha. Investigators postulate that the shed receptors either act as natural antagonists or as a TNF-alpha reservoir extending the half-life of the cognate ligand. Based on these observations, IL-1beta effects on lung TNF-alpha-mediated inflammatory responses, as well as on TNF receptor expression and shedding, both in vitro and in vivo were investigated. Finally, the roles of the two soluble TNF receptors (sTNFR) on altering ligand-induced inflammation and cytotoxicity were analyzed. Studies utilizing an in vitro culture system, murine epithelial type II-like cells (MLE-15), and transgenic IL-1beta null mice showed that the interleukin enhances acute, TNF-alpha-mediated pulmonary inflammatory processes. In vitro, IL-1beta induced MLE-15 surface TNF receptor expression which correlated with increased mRNA levels and protein secretion of the two neutrophil chemoattractants macrophage inflammatory protein (MIP-2) and KC following TNF-alpha exposure. Further studies investigating the regulation of the two receptors demonstrated a counter-regulatory role for each; TNFR1 expression was necessary for interleukin-mediated TNFR2 shedding and surface expression and vice a versa. In vivo studies corroborated these findings. IL-1f3 KO mice instilled with TNF-alpha had decreased neutrophil influx measured in the lavage fluid of the lung. This correlated with a decrease in lavage sTNFR1 and MIP-2, although sTNFR2 and KC were unaffected. Finally, at a ratio of approximately 1:1 to 1:25, sTNFR1:sTNFR2 functioned as TNF-alpha antagonists in vitro . Taken together, the studies in this thesis suggest that IL-1beta modulates TNF-alpha-mediated inflammatory lung diseases by altering TNF receptor shedding and expression in epithelial cells, resulting in altered chemoattractant production in response to TNF-alpha, hence augmenting recruitment of inflammatory cells.