Blocking TNF-α enhances Pseudomonas aeruginosa-induced mortality in burn mice through induction of IL-1β

Purpose: Tumor necrosis factor (TNF alpha) is a proinflammatory cytokine and has been a target for intervention in human sepsis. However, inhibition of TNF-alpha with a high dose of a TNF-receptor fusion protein in patients with septic shock worsened patient survival. This study was designed to investigate whether blocking TNF-alpha enhances mortality in infected burn mice through the induction of IL-1 beta. Methods: WT or Tnfrsf1a(-/-) mice received Pseudomonas aeruginosa injection in the back at 8 h after burn injury. The animals were sacrificed at 24 h after burn and lung tissues were harvested and examined for determining myeloperoxidase (MPO) activity, pulmonary microvascular dysfunction, NP-kappa B DNA binding activity, and IL-1 beta expression. Also, the lung and blood were harvested for bacterial count assay. Result: Thermal injury alone induced NF-kappa B DNA binding activity and neutrophil infiltration in the lung in WT but not in Tnfrsf1a(-/-) mice. A 50% total body surface area (TBSA) burn induced a significant increase of mortality in WT compared with Tnfrsf1a(-/-) mice. In contrast, P. aeruginosa injection with a 30% TBSA burn pretreatment enhanced IL-1 beta expression, bacterial counts in lung and blood, pulmonary microvascular dysfunction, and mortality in Tnfrsf1a(-/-) mice compared with WT mice. Injection of the IL-1 receptor antagonist, Anakinra, reduced P. aeruginosa infection with burn pretreatment-induced blood bacterial counts, IL-1 beta levels as well as permeability of lung, and mortality in Tnfrsf1a(-/-) mice. Conclusions: Our findings suggest that thermal injury induces lung NF-kappa B activation and neutrophil sequestration through TNF alpha signaling. However, blocking TNF-alpha enhances P. aeruginosa infection-induced lung damage in burn mice via induction of IL-1 beta. Using an IL-1 receptor antagonist combined with the neutralization of TNF-alpha could be a useful strategy for decreasing P. aeruginosa infection-induced mortality in burn patients. (c) 2013 Elsevier Ltd. All rights reserved.