IL-13 may mediate allergen-induced hyperresponsiveness independently of IL-5 or eotaxin by effects on airway smooth muscle

Abstract

IL-13 is a mediator of allergen-induced airway hyperresponsiveness (AHR). The aim of this study was to evaluate whether eotaxin and IL-5 were implicated in the effects of IL-13 on allergen-induced AHR or whether IL-13 may exert its effects through direct actions on airway smooth muscle (ASM). To study this question airway inflammation and AHR were induced in mice by sensitization and subsequent challenge on three successive days with ovalbumin. A monoclonal anti-IL-13 antibody administered before each challenge significantly reduced AHR without affecting airway eosinophilia. No changes of mRNA in BAL and lung tissues or protein levels in BAL of IL-5 or eotaxin were found following anti-IL-13 treatment. Combined injection of monoclonal anti-IL-5 and antieotaxin antibodies before each antigen challenge blocked airway eosinophilia but failed to reduce AHR. IL-13 induced calcium transients in cultured murine ASM cells and augmented the calcium and contractile responses of these cells to leukotriene D4. These results suggest that IL-13 plays an important role in allergen-induced AHR and is important in the early phases of the inflammatory process. Its effects on AHR are mediated independently of IL-5 and eotaxin and may involve a direct effect on ASM to augment its responsiveness.

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production

“…IL-13 is a pleiotropic cytokine produced mainly by T cells and is critical for the development of airway hyperresponsiveness (AHR) associated with allergen exposure [18]. It has indeed been reported that treatment of mice with anti-IL-13 mAb inhibited AHR [19,20] and that Il-13-induced airway inflammation might involve a direct effect on airway smooth muscles [21]. Our results strongly suggest that IL-13 production is intrinsically different in the two mouse strains and accounts for the increased bronchial hyperresponsiveness in BALB/c mice.…”

“…Mast cells are also a major source of IL-4, which is increased in those mice after allergen exposure [26]. Nevertheless, other factors than IL-13 or mediators released by mast cells could take part in the hyperresponsiveness in mice since two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced airway hyperresponsiveness, Abhr1 (allergen-induced bronchial hyperresponsiveness) and Abhr2, have been identified on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice [21], suggesting that some genetic factors are also important in the pathogenesis of this phenomenon.…”

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…The accumulation of Mfge8 around smooth muscle and the lack of Mfge8 in the airway epithelium suggested that the effect of Mfge8 on ASM was independent of interactions between ASM and the adjacent epithelium. However, IL-13 affects the airway epithelium (25) and ASM (26), and airway epithelium has an inhibitory effect on ASM contraction (27,28). To investigate whether smooth muscle-epithelial interactions were important for the function of Mfge8 in ASM contraction, we repeated the tracheal ring contraction assay after denuding the epithelium layer from each ring (4).…”

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

“…Ultimately, these processes lead to helper T type 2 (Th2) cell differentiation and further production of the Th2 cytokines IL-4, IL-5, and IL-13 (4-6), and memory T and B cells are generated that can lead to chronic inflammation. Much of the remodeling and dysfunction in resident lung cells that are associated with asthma can be reproduced by IL-13 exposure, including goblet cell metaplasia (7), subepithelial fibrosis (8), and airway hyperresponsiveness (9)(10)(11)(12). IL-4 can mimic many of the effects of IL-13 and is thought particularly important in IgE class switching by B cells.…”