title: Chronic restraint stress promotes immune suppression through toll-like receptor 4-mediated phosphoinositide 3-kinase signaling.
abstract: Stress, either psychological or physical, can have a dramatic impact on the immune system. Toll-like receptors (TLRs) play a pivotal role in the induction of innate and adaptive immune response. We have reported that stress modulates the immune response in a TLR4-dependent manner. However, the mechanisms underlying TLR4-mediated signaling in stress modulation of immune system have not been identified. Here, we demonstrate an essential role for the TLR4-mediated phosphoinositide 3-kinase (PI3K)/Akt signaling. PI3K inhibition by inhibitors wortmannin or LY294002 abrogated protection of stress-induced immune suppression in TLR4-deficient mice compared with TLR4-deficient mice that did not receive the inhibitors. The mechanisms by which PI3K are increased in the TLR4-deficient lymphocytes may involve increased phosphorylation of Akt as well as increased phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta). The stress-mediated suppression of T help 1 (Th1) cytokine and increased production of Th2 cytokine was greatly reduced in TLR4 deficient mice compared with the wild type mice. Moreover, inhibition of PI3K diminished protection of the above Th1 and Th2 changes caused by stress in TLR4-deficient mice compared with non-stressed mice and the wild type mice. Our data demonstrated that TLR4 negatively regulates PI3K activity in wild type mice, leading to the observed the stress-induced immune response. The higher levels of PI3K prevent TLR4 deficient mice from the stress-induced immune response. Therefore, stress modulates the immune system through TLR4-mediated PI3K/Akt signaling.
authors.affiliation: Department of Internal Medicine, James Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Junying
authors.initials: J
authors.lastname: Miao
authors.forename: Gregory
authors.initials: G
authors.lastname: Hanley
authors.forename: Charles
authors.initials: C
authors.lastname: Stuart
authors.forename: Xiuli
authors.initials: X
authors.lastname: Sun
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D007165:Immunosuppression Therapy; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D051197:Toll-Like Receptor 4; D000077191:Wortmannin; C493487:Tlr4 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one