Bone marrow-derived dendritic cells were stimulated with TLR ligands in the presence or absence of lidocaine for 4 h and 24 h for quantitative real-time PCR analysis and cytokine ELISA, respectively. Cytokine ELISA The amount of IL-12p70, TNF-, ILC6, ILC10, IFN, ILC4, ILC5, ILC13 and ILC17 in the cultured supernatant were determined with an ELISA kit (all from Biolegend except ILC13 from eBioscience). TNF and ILC12 from dendritic cells in response to toll-like receptor ligands including lipopolysaccharide, poly(I:C) and R837 in a dose-dependent manner. Notably, the differentiation of Th1 cells was significantly suppressed by the addition of lidocaine while the same treatment experienced little effect on the differentiation of Th17, Th2 and regulatory T cells induced by the adoptive transfer of ovalbumin-pulsed dendritic cells. These results demonstrate that lidocaine inhibits the activation of dendritic cells in response to toll-like receptor signals and subsequently suppresses the differentiation of Th1 cell responses. Introduction Acknowledgement of pathogen-associated molecular patterns (PAMPs) such as toll-like receptor (TLR) ligands as well as damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1) by innate immune receptors leads to the activation of macrophages and dendritic cells [1, 2]. Tissue resident macrophages are known to sense these exogenous and endogenous stimuli to produce immune modulatory molecules such as ILC6, TNF as well as reactive nitrogen species and Allantoin reactive oxygen species that can mediate tissue inflammation [3, 4]. On the other hand, activation of dendritic cells by PAMPs and DAMPs not only triggers the production of pro- or anti-inflammatory cytokines, but also induces their migration into lymph nodes and subsequent activation of T cells in an antigen-specific manner [5, 6]. Depending on the types of cytokines and costimulatory molecules expressed by dendritic cells, the interacting antigen-specific T cells can acquire diverse effector functions. In case of CD4+ T cells, these effector T cells include Th1, Th2, follicular helper T, Th17 and regulatory T cells, all of which that have unique effector functions in adaptive immune arms [7C9]. Hence, modulation of innate immunity in response to PAMPs and DAMPs can determine the type(s) of adaptive immunity as well as that of innate immunity during inflammation. Anesthetic brokers are widely used to reduce pain and psychological stress during a process involving tissue damage including perioperative practice which can trigger the production of DAMPs by damaged cells as well as PAMPs by invading infectious brokers [10]. It is well documented that surgical stress modulates the function of innate immune cells. Allantoin For instance, surgical stress has been shown to mediate endotoxin hypo-responsiveness by increasing the production of ILC10 while decreasing the production of TNF [11, 12]. In addition, a number of anesthetics exhibit immune modulatory activity, either by directly acting on immune cells or indirectly by affecting hypothalamic-pituitary-adrenal axis in experimental animals as well as in humans [13, 14]. In general, anesthetics are known to exert immune suppressive activities in innate immune cells. For instance, lidocaine inhibits phagocytic activity, chemotaxis and activation of human neutrophils [15C18]. Similarly, lidocaine suppresses the production of nitric oxide from murine macrophages upon activation with lipopolysaccharide (LPS) and IFN, possibly through the regulation of voltage-sensitive Na+ channel [19, 20]. Furthermore, administration of lidocaine has been shown to inhibit acute lung injury induced by LPS via suppressing the activation of the NF-B signaling pathway in an animal model of endotoxemia [21]. Similarly, the production of ILC1 and ILC6 as well as the expression of ICAMC1 on activated endothelial cells is usually down-regulated by lidocaine [22]. These immune suppressive activities of anesthetics can be problematic in patients with tumor or infections since the suppression of immune competent arms would be detrimental in fighting against malignancy cells and infectious brokers [23]. Lidocaine is the only local anesthetic that is approved for intravenous administration in clinical practice. Lidocaine has an anti-inflammatory house by attenuation of production of pro-inflammatory cytokines which are known to cause inflammatory and neuropathic pain [24]. Systemic administration of lidocaine reduces Allantoin surgery-induced immune reactions via decreased production of pro- and anti-inflammatory cytokines (ILC6 and IL-1Ra, respectively) during abdominal hysterectomy [25]. Intravenous lidocaine infusion reduces postoperative pain intensity and analgesic Casp3 requirements in patients undergoing abdominal surgery [26]. Perioperative infusion of lidocaine reduces the incidence of post-mastectomy chronic pain [27]. Of notice, lidocaine has been known to induce allergic reactions in humans; while type I or anaphylactic.