title: Estrogen modulates β2-adrenoceptor-induced cell-mediated and inflammatory immune responses through ER-α involving distinct intracellular signaling pathways, antioxidant enzymes, and nitric oxide.
abstract: Sympathetic noradrenergic neuronal activity in the lymphoid organs regulates immunity through the release and binding of norepinephrine to β2-adrenergic receptors (AR) on lymphocytes. In women, estrogen modulates immune responses during menstrual cycles, and in aging and age-associated diseases. The intent of the present study is to characterize the extent of immunomodulation by β2-AR in the presence of estrogen and the involvement of intracellular signaling mechanisms including the role of antioxidant enzymes (AOE) in lymphocytes. In vitro effects of terbutaline, β2-AR agonist, either alone or in combination with 17β-estradiol (E2) were examined on splenocyte proliferation, cytokine (IFN-γ, IL-2, and IL-6) production, intracellular signaling molecules (p-ERK, p-CREB, p-Akt, and p-NF-κB) expression, NO production, and AOE activities [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx)]. The specificity of their actions was investigated using β-AR antagonist, and inhibitors of signaling targets and inducible nitric oxide synthase (iNOS). Terbutaline suppressed T cell proliferation and IL-6 production and increased AOE activities involving ERK, PKA, PKC, and NF-κB pathways and NO production. E2 alone enhanced T cell proliferation and decreased IL-6 production and NF-κB expression through ER-α. E2 in the presence of terbutaline reversed terbutaline-induced effects on T cell proliferation, IL-6 production, p-ERK and p-CREB expression, AOE activities, NO production, and NF-κB expression. Estrogen through ER-α differentially modulates β2-AR-induced immune responses involving ERK, PKA, PKC, and NF-κB pathways, and NO that may be responsible for estrogen-induced immunosenescence and development of female-specific diseases.
authors.affiliation: Integrative Medicine Laboratory, Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603 203, Tamil Nadu, India.
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Priyanka
authors.affiliation: Integrative Medicine Laboratory, Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603 203, Tamil Nadu, India.
authors.forename: Ran Vijay
authors.initials: RV
authors.lastname: Singh
authors.affiliation: Integrative Medicine Laboratory, Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603 203, Tamil Nadu, India.
authors.forename: Uday P
authors.initials: UP
authors.lastname: Pratap
authors.affiliation: Integrative Medicine Laboratory, Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603 203, Tamil Nadu, India. Electronic address: thyagarajan.s@ktr.srmuniv.ac.in.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: ThyagaRajan
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D047628:Estrogen Receptor alpha / Q000276:immunology*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D042541:Intracellular Space / Q000276:immunology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D016207:Cytokines; D047628:Estrogen Receptor alpha; D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase
keywords: 17β-Estradiol; Cytokines; NF-κB; p-Akt; p-CREB; p-ERK