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

R. Rabinovici, G. Feuerstein, F. Abdullah, M. Whiteford, P. Borboroglu, E. Sheikh, D. R. Phillip, P. Ovadia, L. Bobroski, O. Bagasra, L. F. Neville

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)329-336
Number of pages8
JournalCirculation Research
Issue number2
StatePublished - Feb 1996
Externally publishedYes


  • Adult respiratory distress syndrome
  • Cytokines
  • Immunotherapy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Locally Produced Tumor Necrosis Factor-α Mediates Interleukin-2-Induced Lung Injury'. Together they form a unique fingerprint.

Cite this