Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle

Abstract

Interleukin (IL)-1b is a pleiotropic, pro-inflammatory cytokine that has been importantly implicated in driving the inflammatory response and resultant changes in airway smooth muscle (ASM) responsiveness in asthma. IL-1b belongs to a family of molecules, known as the IL-1 axis, which exert both pro-and anti-inflammatory effects. Since dysregulation of IL-1 axis molecules may be critical in the pathobiology of asthma, the present study examined the expression and activation of both the inhibitory and stimulatory IL-1 axis molecules in human ASM cells and their roles in modulating cytokine and immunoglobulin (Ig)E immune complex (IgE cx)-mediated changes in rabbit ASM constrictor and relaxant responsiveness.The results demonstrate the following. 1) Pre-treatment of isolated rabbit tracheal rings with the inhibitory IL-1 axis members, IL-1 receptor antagonist and IL-1 type-II receptor abrogated both IL-5-and IgE cx-induced changes in ASM responsiveness. 2) Administration of IL-5, IL-1b and IgE cxs to human ASM cells increased mRNA and protein expressions of both stimulatory and inhibitory IL-1 axis molecules.3) The time course of IL-5-induced IL-1 axis molecule expression preceded that of both IL-1b and IgE immune cxs.Collectively, these findings suggest that modulation at the level of the interleukin-1 axis of molecules may have significant therapeutic potential in the treatment of asthma.

Asthmatic airway hyperresponsiveness: the ants in the tree

“…Alterations in any of those contractile properties potentially discriminate between hypo-, normo-, and hyper-responsiveness. Many exogenous and endogenous molecules have been shown to reduce responsiveness to bronchodilators -such as RV16 [13], Der p 1 [10], LPS [6], TNFa [41], IL-1b, IL-5 [42], IL-10 [43], IL-13 [44], TGFb1 [45], sphingosine-1-phosphate [46], lysophosphatidylcholine [47], plateletactivating factor, platelet-derived growth factor-AB [48], and b-tryptase [49] -suggesting that those molecules can also compromise airway patency by decreasing the ability of the ASM to relax. Many molecules can also potentiate the contractile effect of spasmogens based on their ability to enhance ASM shortening (not necessarily by increasing ASM force).…”

Dual Role of Interleukin-1α in Delayed-Type Hypersensitivity and Airway Hyperresponsiveness

“…IL-1α caused severe pulmonary infiltration with neutrophils/macrophages and emphysema development in transgenic mice with timed induction of IL-1α expression in lung epithelial cells [37]. In addition, delivery of an adenovirus expressing IL-1RA after sensitization and before airway antigen challenge alleviated AHR, pulmonary infiltration with eosinophils and neutrophils and decreased IL-5 levels [38], IL-1RA abrogated both the IL-5- and IgE-induced changes in airway smooth muscle responsiveness in asthma [39], whereas, in contrast, IL-1β and TNF-α increased airway smooth muscle response to various contractile agonists, e.g. methacholine [40].…”

Prevention of IL-1 signaling attenuates airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate–induced asthma

“…10-13 IL-1 receptor type Ideficient mice (IL-1Rko) demonstrate reduced eosinophil recruitment to the bronchoalveolar lavage fluid (BALF) and lung tissue, 10 reduced ovalbumin-specific antibody production in mild asthma, 11 and reduced airway hyperresponsiveness (AHR) and T H 2 cytokine production after challenge in ovalbumin-sensitized mice. 12 The involvement of IL-1 in eosinophilic lung inflammation and AHR are supported by observations that IL-1 stimulates the release of IL-5 from airway smooth muscle cells, 13 a T H 2 cytokine important for eosinophil recruitment and activation, and induces endothelial cell production of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). 14,15 In this respect the expression of IL-1b, ICAM-1, and VCAM-1 are increased after TDI challenge in sensitized mice.…”