Bronchial asthma is a type of airway allergic inflammation disease caused by variety of inflammatory cells and mediators. Inflammatory cells and released mediators played an important part in the complicated pathogenesis of asthma [
29,
30]. Thereby, in this article, we principally focus on the mechanism of OX40L in asthma. In our study, we found that OX40L was significantly higher in patients with asthma, suggesting the possibility that OX40L was associated with asthma. There were a few articles have confirmed this point, such as, Ezzat et al. found the mean and median of OX40L levels were dramatically higher in asthmatic children during acute attacks children than in children with moderate mild asthma exacerbations [
31] and Siddiqui et al. showed the number of OX40, OX40L and IL-4 were significantly increased in subjects with mild asthma compared with healthy controls [
1]. Moreover, we also found that the OX40L was increased in mononuclear cells stimulated with OVA, suggesting that OX40L played a significant role in the asthma response induced by helper T cells. Specifically, OX40/OX40L interactions played a potential role in differentiation of T cells and has an influence on the balance of Th1/Th2 [
32]. Note that OX40L can activate the expression of IL-4 by T cell, inhibit the expression of IFN-γ and participate in the immunocyte including mastocyte mediated Th2-type immune response [
33]. In addition, the expression of OX40 induced by Th17 cells and signaling through OX40 also contributes to Th17-type immune response [
34] and costimulatory receptor OX40L can prevent differentiation of Tregs and block their function [
35]. Moreover, the signaling pathways involved in asthma, for instance, tyrosine kinase signaling cascades played a vital role in allergic airway inflammation [
36], and GM-CSF activation of STAT5 pathway delayed apoptosis of lung granulocytes in this asthma [
37]. In addition, TGF-beta signaling was active in asthmatic airways and the activity was associated with the development of airway remodeling in asthma [
38]. Similarly, PI3K/AKT and MAPK were tightly associated with asthma. Various studies have shown that PI3K/AKT pathway was linked to the development of asthma and inhibition of PI3K/AKT signaling might attenuate allergic asthma [
39]. It has also been demonstrated that p38 MAPK pathway regulated the expression of IL-4 and IL-5 at the levels of mRNA and protein, which played a crucial role in the pathogenesis of asthma [
40]. Subsequently, we examined whether preventive effect of PI3K/AKT and p38 MAPK inhibition on OX40L in asthma could be via PI3K-AKT and p38 MAPK pathway. Our results demonstrate that OX40L significantly activated PI3K, AKT and P38 MAPK protein kinases in asthma which were significantly prevented by inhibitors of PI3 K and p38 MAPK. These observations suggest that PI3K/AKT and p38 MAPK would have a suppressive impact on differentiation of helper T cells and OX40L induced differentiation of helper T cells through PI3K/AKT and p38 MAPK signaling pathway.
Furthermore, we investigated the role of OX40L in asthma using a mouse asthma model in vivo, and the interaction of OX40/OX40L indeed tightly associated with asthma in differentiation of helper T cells. This study provides a more innovative and comprehensive understanding of OX40/OX40L in regulating differentiation of helper T cells in asthma, which also provide novel insight for asthma prevention and possible target for drug development.