Abstract
NK-4 is the main component of the antiallergic drug Lumin, which has been in popular usage since the early 1950s. In this study, we examined whether NK-4 exerts a regulatory effect on the activation and effector function of Th2 cells. NK-4 inhibited IL-4 production by anti-CD3ε mAb-stimulated BALB/c mouse spleen cells, whereas NK-4 had little effect on IFN-γ production. IL-4 and IL-5 secretion by anti-CD3ε mAb- or antigen-stimulated Th2 cells (D10.G4.1) was abrogated by NK-4 without affecting cell numbers, whereas IFN-γ secretion by activated Th1 cells was unchanged. Mechanistic analysis revealed that NK-4 inhibited mRNA expression of the Th2-associated transcription factors GATA-3 and NFATc1 in anti-CD3ε mAb-stimulated D10.G4.1 cells. Regarding the regulation of Th2 cell effector functions, NK-4 inhibited the secretion of eotaxin and thymus and activation-regulated chemokine (TARC) by normal human dermal fibroblasts in response to IL-4 and/or TNF-α. NK-4 achieved TARC attenuation comparable to what is observed with suplatast tosilate, an antiallergic drug that selectively inhibits Th2 cytokine production, at 14-fold lower concentrations of suplatast tosilate. Dexamethasone increased TARC production by 2.2- to 2.6-fold of control cultures. NK-4 successfully inhibited the STAT6 signaling pathway, suggesting a potential mechanism for down-regulating chemokines expression. In addition, NK-4 abrogated IL-4-driven modulation of cytokine production profile in human monocytic THP-1 cells from proinflammatory to anti-inflammatory response, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. These results suggest that NK-4 could prevent IL-4-driven polarization to alternatively activated macrophages, which are proposed to have pathogenic roles in allergic asthma. The importance of Th2 cytokines and chemokines in the development and progression of type 2 inflammatory disorders has been highlighted by recent advance in our understanding the immunological mechanism underlying allergic disease. Our results support the use of NK-4 as a reasonable therapeutic option to alleviate Th2-mediated allergic inflammation.
Highlights
CD4+ effector T helper (Th) cells play central roles in host defense against a range of invading pathogens
Since Th2 cytokine-selective down-regulation was observed with NK-4, we examined whether NK-4 modulates the effector function of IL-4 and TNF-α, both of which are produced by activated Th2 cells, mast cells and basophils in the course of allergic inflammatory responses [6, 7]
We examined whether NK-4 has a regulatory effect on Th1/Th2 cytokine production by primary T cells
Summary
CD4+ effector T helper (Th) cells play central roles in host defense against a range of invading pathogens. Th1 cells that secrete IFN-γ upon antigenic stimulation have a critical role in the eradication of intracellular pathogens, since IFN-γ produced by Th1 cells is a key factor in the elimination of intracellular pathogen by increasing the level of cellular reactive oxygen species (ROS) [3]. The host immune system promotes Th2 commitment by naïve Th cells. Th2 cells and IgE-bound mast cells are activated by helminth-derived antigens and promote the accumulation of eosinophils and basophils through the secretion of Th2 cytokines and chemokines. IgE promotes parasite expulsion from the gut and regulates mast cell responses against helminths [5]. Eosinophils are well-known to accumulate around helminths and to release ROS and toxic granular proteins upon stimulation
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