Tumor necrosis factor-alpha mediates lipopolysaccharide-induced macrophageinflammatory protein-2 release from alveolar epithelial cells - Autoregulation in host defense

Our recent studies have demonstrated that in response to lipopolysaccharide (LPS) challenge, alveolar epithelial cells produced tumor necrosis factor (TNF)-alpha, an early response cytokine in the inflammatory process. To inv estigate whether LPS-induced TNF-alpha release is related to other inflamma tory mediators from the same cell type, we examined effects of LPS stimulat ion on macrophage inflammatory protein (MIP)-2 production by alveolar epith elial cells, and then examined the relationship between TNF-alpha and MIP-2 production. LPS stimulation induced a dose- and time-dependent release of MIP-2. The steady-state messenger RNA level of MIP-2 was significantly incr eased, with the MIP-2 protein localized within alveolar epithelial cells, a s determined by confocal microscopy. The LPS-induced MIP-2 production is re gulated at both the transcriptional and post-transcriptional levels. TNF-al pha also induced MIP-2 production from alveolar epithelial cells. Preincuba tion with an antisense oligonucleotide against TNF-alpha inhibited LPS-indu ced TNF-alpha in a dose-dependent and sequence-specific manner. The same an tisense also inhibited MIP-2 production. The inhibitory effects were highly correlated. Polyclonal and monoclonal antibodies against TNF-alpha also at tenuated LPS-induced MIP-2. These results suggest that LPS-induced MIP-2 re lease from alveolar epithelial cells may be mediated in part by TNF-alpha f rom the same cell type. This autoregulatory mechanism may amplify LPS-induc ed signals involved in host defense as well as in acute inflammatory reacti ons.