Abstract
BackgroundThe aim of this study was to investigate the mechanisms of OX40L in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments.MethodsSerum samples of patients with asthma and healthy controls were used to explore the association between OX40L and Th cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of OX40L, IL-4, IFN-γ, IL-17 and TGF-β. Flow cytometry method was used to analyze Th1, Th2, Th17 and Treg cells. 3H-thymidine was used to determine the proliferation of T cells. Western Blot was used to detect protein expression and phosphorylation. Immunohistochemistry was used to detect the expression of OX40L in lung tissues.ResultsOX40L, IL-4, IL-17 increased in patient serum compared to healthy control and in the ovalbumin (OVA)-primed mononuclear cells compared to normal cells, while IFN-γ and TGF-β were decreased. Besides, the OVA-primed CD4+ T cells treated with OX40L-Ig fusion protein promoted the proliferation of T cells and Th2 and Th17 cells differentiation as well as PI3K/AKT and p38 MAPK signaling pathway, but suppressed Th1 and Treg cells differentiation. Moreover, helper T cells differentiation in OVA-primed CD4+ T cells could be markedly reversed by the addition of PI3K/AKT inhibition, p38 MAPK inhibition and anti-OX40L monoclonal antibody.ConclusionsIn this study, we revealed that OX40L could regulate differentiation of helper T cells via PI3K/AKT and p38 MAPK signaling pathway in asthma. Besides, blockade of OX40/OX40L could inhibit the proliferation of CD4+ T cells and regulate polarization of helper T cells.
Highlights
The aim of this study was to investigate the mechanisms of OX40 ligand (OX40L) in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments
As shown in Fig. 3j, we found that the level of phosphorylation of AKT and p38 MAPK were elevated in OVA-challenged CD4+ T cells, and more elevated in OVA-challenged CD4+ T treated with OX40L-Ig fusion protein
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]
Summary
The aim of this study was to investigate the mechanisms of OX40L in regulating helper T (Th) cells differentiation through phosphoinositide 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase signaling pathway in vitro and in vivo experiments. Some studies have suggested that dysfunction of helper T cells plays a key role in allergic asthma, OX40L–OX40 interactions contribute to the differentiation of helper T. The imbalance and function of T-helper type Th1/Th2 were perceived as the crucial pathogenesis of asthma [8]. Th2-type immune response is mediated by cytokines including IL-4 will facilitate the occurrence of the aeroallergen and hyperresponsiveness [10]. The imbalance between Th17 and Treg could play a crucial role in allergic airway inflammation [13]. It has been known that Th17 cells play significant roles in airway hyperresponsiveness and typically promote neutrophilic inflammation in accordance with Th2 cells [14]. OX40/OX40L plays a crucial role in regulating the balance of Th1/Th2 and Th17/Treg in asthma [16]
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