Cysteinyl leukotrienes induce nuclear factor κb activation and rantes production in a murine model of asthma☆

Abstract 

Background: It has been demonstrated that both cysteinyl leukotrienes (cysLTs) and cytokines are involved in the pathophysiology of bronchial asthma. Nonetheless, the exact mechanism involved in the interaction between these 2 molecules has yet to be determined. Objective: The aim of the present study was to determine the effects of cysLTs on allergic airway inflammation and allergen-specific cytokine production in a murine model of asthma. Methods: Four groups of BALB/c mice (control mice, Dermatophagoides farinae allergen-sensitized mice, pranlukast cysLT receptor antagonist-treated allergen-sensitized mice, and dexamethasone-treated allergen-sensitized mice) were examined. Results: Allergen-sensitized mice exhibited increased airway responsiveness and inflammation. Pranlukast-treated mice showed significant attenuation of these changes concomitant with reduction of T_H2 cytokine and IFN-γ production by isolated lung mononuclear cells (MNCs). A much stronger inhibition of all cytokines was noted in dexamethasone-treated mice. Pranlukast also significantly inhibited production of RANTES and activation of nuclear factor κB (NF-κB) in the isolated lung MNCs. Leukotriene D₄ stimulated isolated lung MNCs to produce RANTES but not any other cytokines and also activated NF-κB in these cells. Conclusions: Our results suggest that cysLTs activate NF-κB and induce RANTES production from isolated lung MNCs, which in turn might cause migration of eosinophils and activated T lymphocytes into the airway. (J Allergy Clin Immunol 2003;112:369-74.)

Keywords:  Leukotrienes, cytokines, nuclear factor κB, RANTES, inflammation

Abbreviations:  AHR , Airway hyperresponsiveness, CysLT , Cysteinyl leukotriene, LTD₄, Leukotriene D₄, MNC , Mononuclear cell, NF-κB , Nuclear factor κB, sRAW , Specific airway resistance