Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules， CD28 signaling and cytokine production in stress-induced immune responses.

Recently， the expression of histamine 4 receptor (H4R) on neurons was reported， however its function in cells within the central nervous system (CNS) remains poorly understood. To this end， we used the H4R agonist， 4-methylhistamine (4-MeH)， and the H4R antagonist， JNJ77777120 (JNJ)， to investigate the function of H4R signaling in immune cells in a murine model of chronic stress. Treatment of stressed mice with 4-MeH resulted in an increase in the proportion of lymphocyte subsets (CD3(+)， CD8(+)， CD28(+)， and CD4(+)CD28(+)) and cells expressing the co-stimulatory molecules CD80(+) (B7.1) and CD86(+) (B7.2) in heparinized blood as compared to normal control (NC) and stressed control (SC) groups. We also observed that as compared to NC and SC mice， 4-MeH-treated mice showed greater production of IL-2(+)， IL-6(+)， IL-9(+)， IL-21(+)， and IL-27(+) cytokines in the spleen and by splenic CD4(+) T cells. Furthermore， 4-MeH treatment of stressed mice led to an increase in the levels of serum Th1/Th17 cytokines and corticosterone， and a decrease in Th2 cytokines. Treatment of chronically-stressed mice with 4-MeH also augmented expression of IL-6， IL-21， NF-κB p65， and STAT3 mRNA. Moreover， Western blot analyses confirmed increased protein expression of NF-κB， iNOS， and STAT3 expression following 4-MeH treatment of chronically-stressed mice as compared to controls. These proteins provide a novel relevant targets for the manipulation of chronic stress induced immune regulation. In striking contrast， treatment of stressed mice with the H4R antagonist， JNJ， resulted in a substantial reduction in all of the aforementioned effects upon immune cell percentages and cytokine production.