IL-1β Augments TNF-α–Mediated Inflammatory Responses from Lung Epithelial Cells

Abstract

Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) mediate the development of numerous inflammatory lung diseases. Since IL-1β is typically activated in situations where TNF-α is produced, it was hypothesized that IL-1β alters TNF-α–induced proinflammatory epithelial cell function by altering TNF receptor shedding and surface abundance. In this study, the impact of IL-1β on TNF-α–mediated chemokine production as well as TNF receptor surface expression and shedding were investigated from mouse pulmonary epithelial cells (MLE-15). Interleukin-1β rapidly and persistently enhanced soluble and surface TNFR2. These effects were dependent on TNFR1 expression. TNFR2 small-interfering RNA (siRNA) shifted IL-1β responses, significantly increasing surface and shed TNFR1 implying IL-1β selectively modifies TNF receptors depending on cellular receptor composition. mRNA expression of both receptors was unaltered by IL-1β up to 24 h or in combination with TNF-α indicating effects were post-transcriptional. Interleukin-1β pretreatment enhanced TNF-α–induced macrophage inflammatory protein (MIP)-2 and KC mRNA expression as well as MIP-2 and KC protein levels at the same time point analyzed. Experiments utilizing siRNA against the TNF receptors and a TNFR1 neutralizing antibody demonstrated TNF-α induced MIP-2 through TNFR1, whereas both receptors may have contributed to KC production. These data suggest IL-1β modulates TNF-α–mediated inflammatory lung diseases by enhancing epithelial cell TNF receptor surface expression.