Hyaluronic acid targets CD44 and inhibits FcεRI signaling involving PKCδ, Rac1, ROS, and MAPK to exert anti-allergic effect

초록

Effects of hyaluronic acid (HA) on allergic inflammation were investigated. HA exerted negative effects on beta-hexoaminidase secretion and histamine release in antigen-stimulated rat basophilic leukemia (RBL2H3) cells. HA inhibited interaction between IgE and Fc epsilon RI and between Fc epsilon RI and PKC delta. HA inhibited CD44 interaction with PKC alpha, indicating that HA targets CD44. PKC alpha and -delta were responsible for increased Rac1 activity and expression of p47(phox), p67(phox). HA inhibited phosphorylation of PKC alpha and -delta. Rac1 was responsible for increased ROS, and NADPH oxidase was the main source for ROS. The inhibition of PKC prevented antigen from increasing phosphorylation of ERK and p38 MAPK. ERK, p38 MAPK, and ROS, were responsible for secretion of beta-hexosaminidase, histamine release, and induction of chemokines. HA suppressed induction of chemokines, such as MIP-2 and Sprr-2a. CD44 mediated effect of antigen on phosphorylation of ERK, p38MAPK, ROS production, secretion of beta-hexosaminidase, and histamine release. GPCR did not mediate allergic function of antigen or affect anti-allergic function of HA. In vivo anti-allergic effect of HA was investigated using Nc/Nga mice model of DNFB-induced atopic dermatitis. HA reduced skin lesions in Nc/Nga mice treated with DNFB, decreased expression levels of MIP-2, Sprr-2a, and serum IgE level. In conclusion, hyaluronic acid exerts negative effect on allergic inflammation by targeting CD44 and inhibiting Fc epsilon RI signaling. (C) 2008 Elsevier Ltd. All rights reserved.

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