title: Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance.
abstract: Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest. The effects of treatment with 4-MeH (30mg/kg, i.p., twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4(+) T cell production, and intracellular IFN-γ and IL-4 expression in these cells. We also assessed IL-1β, IFN-γ, TNF-α, and IL-4 mRNA expression as well as IFN-γ, TNF-α, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4(+) T cells as well as in IFN-γ production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1β, IFN-γ and TNF-α mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-γ, TNF-α, GITR, Ox40 and increased IL-4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia. Electronic address: s_fayazahmad@yahoo.com.
authors.forename: Sheikh Fayaz
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cairo, Egypt.
authors.forename: Khairy M A
authors.initials: KM
authors.lastname: Zoheir
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Mushtaq Ahmad
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Abdelkader E
authors.initials: AE
authors.lastname: Ashour
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
mesh_terms: D000818:Animals; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics; D017442:Histamine Agonists / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015847:Interleukin-4 / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis; D011968:Receptors, Histamine / Q000276:immunology*; D012149:Restraint, Physical; D013154:Spleen / Q000276:immunology; D013312:Stress, Physiological / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation
chemical_list: D017442:Histamine Agonists; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008761:Methylhistamines; D012333:RNA, Messenger; D011968:Receptors, Histamine; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; C025566:4-methylhistamine; D007371:Interferon-gamma; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)
keywords: 4-Methylhistamine dihydrochloride; Chronic stress; Cytokines; Histamine 4 receptor; Protein and mRNA expression levels