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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-3β (GSK-3β). 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 nonstressed 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.

Opioids are powerful pain relievers, but also potent inducers of dependence and tolerance. Chronic morphine administration (via subcutaneous pellet) induces morphine dependence in the nucleus accumbens, an important dependence region in the brain, yet the cellular mechanisms are mostly unknown. Toll-like receptor 2 (TLR2) plays an essential function in controlling innate and inflammatory responses. Using a knockout mouse lacking TLR2, we assessed the contribution of TLR2 to microglia activation and development of morphine dependence. We report here that mice deficient in TLR2 inhibit morphine-induced the levels of microglia activation and proinflammatory cytokines. Moreover, in TLR2 knockout mice the main symptoms of morphine withdrawal were significantly attenuated. Our data reveal that TLR2 plays a critical role in morphine-induced microglia activation and dependence. Keywords TLR2; morphine; microglia; cytokines; dependence Opioids have been used as potent analgesics for centuries, but their abuse has deleterious physiological effects and can cause dependence. Opioid dependence, including morphine dependence, is a chronic, relapsing disease. Opioids such as morphine have different effects on the immune response based on the dosage and the number of exposures. We have reported that chronic morphine exposure, such as occurs in drug abuse, inhibits immune function and increases susceptibility to diseases [1][2][3]. Recent evidence indicates that the innate immune responses contribute to the development of opioid dependence and withdrawal [4][5][6]. Opioid dependence and withdrawal significantly increases the production of pro-inflammatory cytokines interleukin-1 (IL-1) and 7]. These pro-inflammatory Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Microglial cells represent the resident immune host defense and are considered the major immune inflammatory cells of the CNS. TLR2 mediated signaling contributes to the impact on the CNS autoimmune diseases and inflammation [15]. However, roles of TLR mediated immune and inflammatory responses in glial activation during the development of opioid dependence remain to be elucidated. We investigated the role of TLR2 in microglia activation and morphine dependent. In present study we found that TLR2 is required for morphine-induced microglia activation and inflammatory responses. Furthermore, in TLR2 knockout mice the main symptoms of morphine withdrawal were significantly attenuated. Our data demonstrate that TLR2 plays a critical role in opioid dependence-mediated microglia activation. NIH Public Access Animals and reagent...

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