Am. J. Respir. Cell Mol. Biol., Volume 21, Number 4, October, 1999 510-520

Tumor Necrosis Factor- Mediates Lipopolysaccharide-Induced Macrophage Inflammatory Protein-2 Release from Alveolar Epithelial Cells
Autoregulation in Host Defense

Alexandre M. Xavier, Noritaka Isowa,^* Lu Cai, Ewa Dziak, Michal Opas, Donna I. McRitchie, Arthur S. Slutsky, Shaf H. Keshavjee, and Mingyao Liu

Thoracic Surgery Research Laboratory, Toronto Hospital; and Departments of Surgery, Medicine, and Anatomy and Cell Biology, University of Toronto, Toronto, Canada

Our recent studies have demonstrated that in response to lipopolysaccharide (LPS) challenge, alveolar epithelial cells produced tumor necrosis factor (TNF)-, an early response cytokine in the inflammatory process. To investigate whether LPS-induced TNF- release is related to other inflammatory mediators from the same cell type, we examined effects of LPS stimulation on macrophage inflammatory protein (MIP)-2 production by alveolar epithelial cells, and then examined the relationship between TNF- 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 increased, with the MIP-2 protein localized within alveolar epithelial cells, as determined by confocal microscopy. The LPS-induced MIP-2 production is regulated at both the transcriptional and post-transcriptional levels. TNF- also induced MIP-2 production from alveolar epithelial cells. Preincubation with an antisense oligonucleotide against TNF- inhibited LPS-induced TNF- in a dose-dependent and sequence-specific manner. The same antisense also inhibited MIP-2 production. The inhibitory effects were highly correlated. Polyclonal and monoclonal antibodies against TNF- also attenuated LPS-induced MIP-2. These results suggest that LPS-induced MIP-2 release from alveolar epithelial cells may be mediated in part by TNF- from the same cell type. This autoregulatory mechanism may amplify LPS-induced signals involved in host defense as well as in acute inflammatory reactions.

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