Cytokines Contribute to Airway Dysfunction in Antigen-challenged Guinea Pigs: Inhibition of Airway Hyperreactivity, Pulmonary Eosinophil Accumulation, and Tumor Necrosis Factor Generation by Pretreatment with an Interleukin-1 Receptor Antagonist

Abstract

The role of pro-inflammatory cytokines in an animal model of allergic lung disease was examined by use of an interleukin-1 receptor antagonist (IL-1ra) and a specific bioassay for tumor necrosis factor (TNF). Ovalbumin-sensitized guinea pigs exhibit a marked bronchial hyperreactivity (assessed by airway responsiveness to intravenous histamine) and pulmonary eosinophil accumulation (assessed by bronchoalveolar lavage) 24 h after challenge with aerosolized antigen. Exposure of animals to an aerosol of IL-1ra (50 micrograms over 30 min) immediately before antigen challenge resulted in a marked protection against bronchial hyperreactivity and pulmonary eosinophil accumulation compared with IL-1ra vehicle-pretreated animals. Additionally, we report for the first time generation of TNF bioactivity in the bronchoalveolar lavage of antigen-challenged animals, which was significantly reduced in animals exposed to aerosolized IL-1ra before challenge. These studies point to a key role for the cytokines IL-1 and possibly TNF in the pulmonary changes observed during allergic airway disease.

Elevation of serum soluble tumour necrosis factor (TNF) receptor and IL-1 receptor antagonist levels in bronchial asthma

“…The elevation of sTNF-R and IL-1Ra in plasma/serum and biological fluids reflecting a variety of inflammatory disorders has been shown in several diseases [24][25][26][27][28]. In addition, protective and inhibitory effects of sTNF-R and IL-1Ra against several inflammatory diseases have been shown [17,18,[29][30][31]. In allergic inflammatory disease, inhibitory effects of IL-1Ra against bronchial hyperreactivity [17], IgE synthesis and allergenspecific production of cytokines such as IL-1 , TNF-, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) [36] have been shown.…”

“…In addition, protective and inhibitory effects of sTNF-R and IL-1Ra against several inflammatory diseases have been shown [17,18,[29][30][31]. In allergic inflammatory disease, inhibitory effects of IL-1Ra against bronchial hyperreactivity [17], IgE synthesis and allergenspecific production of cytokines such as IL-1 , TNF-, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) [36] have been shown. Taken together with inhibitory effects of sTNF-R and IL-1Ra, and our results demonstrating the elevation of serum sTNF-R and IL-1Ra levels during asthma attacks, sTNF-R and IL-1Ra may serve to limit the activity of TNF-and IL-1, and thus may regulate allergic inflammation in bronchial asthma.…”

“…The elevation of these cytokine inhibitors in serum/plasma and biological fluids in several diseases [24][25][26][27][28], and the inhibitory and protective effects of these cytokine inhibitors against IL-1-and TNF--mediated diseases, have been demonstrated [17,18,[29][30][31]. Although up-regulation of TNF-and IL-1 in bronchial asthma has been demonstrated, serum sTNF-R and IL-1Ra levels have not been elucidated.…”

Modulation by IL-10 of antigen-induced allergic responses in mice

“…The participation of TNF-α in allergic reactions is linked to different observations, including its release by mast cells, basophils and alveolar macrophages upon IgE-dependent mechanisms (Burd et al 1989, Gordon & Galli 1990, Ohno et al 1990, Gosset et al 1991. High levels of TNF-α have been shown in monocytes and epithelial cells from asthmatics (Mattoli et al 1991) and BAL fluid from antigen-challenged guinea-pigs (Watson et al 1993). Finally, treatment of sensitized guinea-pigs with an IL-1 receptor antagonist prevents antigeninduced eosinophil accumulation and TNF-α generation in the BAL fluid (Watson et al 1993), indicating that TNF-α may modulate allergic airway inflammation.…”

“…High levels of TNF-α have been shown in monocytes and epithelial cells from asthmatics (Mattoli et al 1991) and BAL fluid from antigen-challenged guinea-pigs (Watson et al 1993). Finally, treatment of sensitized guinea-pigs with an IL-1 receptor antagonist prevents antigeninduced eosinophil accumulation and TNF-α generation in the BAL fluid (Watson et al 1993), indicating that TNF-α may modulate allergic airway inflammation. We thus investigated whether antigen challenge induced the release of this cytokine in the BAL fluid of sensitized mice and verified the potential modulatory activity of IL-10 in this process.…”