Tumor necrosis factor α plus interleukin 1β treatment protects granulocytopenic mice fromPseudomonas aeruginosalung infection: Role of an unusual inflammatory response

Abstract

We have recently demonstrated that treatment with interleukin 1β (IL‐1β) plus tumor necrosis factor a (TNFα) protects granulocytopenic hosts from Pseudomonas aeruginosa aerosol challenge. In this study we characterized the inflammatory response induced by P. aeruginosa in granulocytopenic mice treated with 2,000 U IL‐1β plus 2,000 U TNFα. Treatment with the nonsteroidal anti‐inflammatory agent piroxicam abolished both the protective effect of cytokine treatment and the increase in myeloperoxidase (MPO) pulmonary activity. Histopathological studies revealed that, after aerosol challenge with P. aeruginosa, treatment with these cytokines induced migration and extravasation of mononuclear cells of immature appearance into the lung parenchyma. These cells contained MPO in their cytoplasm and displayed phagocytic capacity. Resident alveolar macrophages exhibited signs of activation and appeared in reduced numbers in bronchoalveolar lavage fluid. We suggest that the inflammatory response promoted by low TNFα plus IL‐1β doses may be one mechanism responsible for protection of granulocytopenic hosts from P. aeruginosa aerosol challenge.

G551D Cystic Fibrosis Mice Exhibit Abnormal Regulation of Inflammation in Lungs and Macrophages

“…Excess induction of TNF-␣ could contribute directly to lung pathology in CF, as this molecule acts as a proximal inflammatory mediator which triggers a cascade of other inflammatory factors and leads to the recruitment and activation of neutrophils (38 -40). Induction of TNF-␣ production is a crucial determinant of the protective inflammatory response to P. aeruginosa challenge in mouse lung (41,42) and others have found that CF mouse lung displays a hyperinflammatory response to such a challenge (15).…”

Consideration of Cytokines as Therapeutics Agents or Targets

“…Interleukins IL-1α/β, 2, 3, 4,5,6,7,8,9,10,11,12,13,15,16,17,18 Interferons IFN-α, β, γ, Ω Anti-infection Cytokines [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] INFα/β/γ, IL-12, G-CSF, M-CSF, GM-CSF, IL-2, TNFα, IL-1, IL-18 [46][47][48][49][50][51] Anti-inflammatory cytokines IL-10, IL-4, IL-13, IL-6, TGFβ1 Cytokine inhibitors soluble (s) IL-1R, sTNFαR, sIFNγR, sIL-4R, sIL-5R; IL-1R antagonist (IL-1Ra), autoantibodies, α 2 -macroglobulin, uromodulin the boundary between these families. In this regard, several classes may be envisioned according to their specific therapeutic applications (Table 2): 1) anticancer cytokines including immune-enhancing cytokines and angiostatic factors; 2) cytokines for wound healing including both growth and angiogenic factors; 3) anti-infection cytokines primarily including virus-lytic and immuneenhancing cytokines; 4) anti-immune-inflammatory cytokines and cytokine inhibitors.…”

“…Recombinant GM-CSF, IFNγ, TNFα or its agonist, IL-1, G-CSF and IL-12 were used to enhance host defense against Streptococcus, Salmonella, Pseudomonas, Klebsiella and Chlamydia bacterial and mycobacterial infections [36,[41][42][43]45]. Reombinant GM-CSF, SCF, G-CSF, IFNγ and IL-12 are among those used in models of fungal infections [33,37,44].…”