Locally Produced Tumor Necrosis Factor-α Mediates Interleukin-2Induced Lung Injury

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Abstract
Interleukin (IL)-2–induced microvascular lung injury is an experimental paradigm commonly used to investigate the pathogenesis of the adult respiratory distress syndrome. Since tumor necrosis factor-α (TNF-α) is known to induce such an injury in vivo and since TNF-α is involved in other models of lung injury, we postulated that it might also mediate pulmonary toxicity after IL-2 administration. The present study tested this hypothesis by evaluating the effect of TNF-α inhibition on IL-2–induced lung injury in the rat. Recombinant human IL-2 (106 U IV per rat, n=6) elevated lung water, myeloperoxidase activity, and protein accumulation in bronchoalveolar lavage fluid and induced tissue hypoxia. Also, IL-2 enhanced lung tissue TNF-α mRNA and peptide (1543±496 pg/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-α, which remained at undetectable levels. Pretreatment with anti–TNF-α monoclonal antibody (25 mg/kg IV, n=7) or the TNF-α synthesis inhibitor rolipram (200 μg/kg IV, n=7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-α inhibition prevented the upregulation of lung tissue IL-1β, IL-6, cytokine-induced neutrophil chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion molecule-1 mRNAs in response to IL-2. These data imply that locally produced TNF-α mediates IL-2–induced lung inflammation and tissue injury and point to the potential utilization of TNF-α inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.

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