Ascaris suum infection modulates inflammation: Implication of CD4+ CD25high Foxp3+ T cells and IL‐10

Helminth infections have the ability to modulate host's immune response through mechanisms that allow the chronic persistence of the worms in the host. Here, we investigated the mechanisms involved on the suppressive effect of Ascaris suum infection using a murine experimental model of LPS‐induced inflammation. We found that infection with A. suum markedly inhibited leucocyte influx induced by LPS into air pouches, suppressed secretion of pro‐inflammatory cytokines (IL‐1β, TNF‐α and IL‐6) and induced high levels of IL‐10 and TGF‐β. Augmented frequency of CD4⁺ CD25^high Foxp3⁺ T cells was observed in the mesenteric lymph nodes of infected mice. Adoptive transfer of purified CD4⁺ CD25⁺ T cells to recipient uninfected mice demonstrated that these cells were able to induce a suppressive effect in the LPS‐induced inflammation in air pouch model. In addition, adoptive transfer of CD4⁺ CD25⁺ T cells derived from IL‐10 knockout mice suggests that this suppressive effect of A. suum infection involves IL‐10 cytokine. In conclusion, our results demonstrated that A. suum experimental infection was capable of suppressing LPS‐induced inflammation by mechanisms, which seem to be dependent on responses of CD4⁺ CD25⁺ T cells and secretion of IL‐10 cytokine.     

Effect of single‐dose DPP‐4 inhibitor sitagliptin on β‐cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug‐naïve,well‐controlled type 2 diabetes subjects

To explore the effects of a single dose of the DPP‐4 inhibitor sitagliptin on glucose‐standardized insulin secretion and β‐cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug‐naïve, well‐controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β‐cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β‐cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β‐cell glucose sensitivity. Sitagliptin also increased active glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) and reduced total (reflecting the secretion) GIP, but not total GLP‐1 levels. We conclude that a single dose of DPP‐4 inhibition induces dissociated effects on different aspects of β‐cell function and incretin hormones after meal ingestion in both healthy and well‐controlled T2D subjects.     

The immunosuppressant drug,thalidomide, improves hepatic alterations induced by a high‐fat diet in mice

Background: Pro‐inflammatory cytokines, such as tumour necrosis factor (TNF)‐α, are known to be involved in the establishment of insulin resistance. Insulin resistance plays a key role in the development of obesity‐related pathologies, such as type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD). The state of chronic inflammation associated with obesity led us to hypothesize that TNF‐α blockade may have an effect on experimentally obese animals. Aims: We studied the effects of thalidomide, an immunosuppressant and anti‐TNF‐α drug, on hepatic alterations that were induced by a high‐fat diet (HFD) in mice. Methods: Obesity was induced in Swiss mice using a HFD for 12 weeks. Thalidomide‐treated animals received thalidomide i.p. (100 mg/kg/day, 10 days). Glucose, aspartate aminotransferases and alanine aminotransferases levels were assessed in the blood. Insulin and glucose tolerance tests were performed. The liver was excised for histological, triglyceride, gene and protein expression analyses. Results: We found improvements in both the basal glucose blood levels and the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of the hepatic insulin receptor substrate (IRS)‐1 and AKT phosphorylation. The hepatic expression of TNF‐α was inhibited and the levels correlated with a significant reduction in the steatosis area. Other hepatic inflammatory markers, such as iNOS and suppressor of cytokine signalling (SOCS‐3), were also reduced. Conclusions: We suggest that immunosuppressant drugs that target TNF‐α and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.     

Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase‐1 expression and up‐regulates matrix metalloproteinase‐9 in toxic liver injury

Abstract: Background: Tissue inhibitor of metalloproteinases (TIMP)‐1, the most important endogenous inhibitor of matrix metalloproteinases, plays a pivotal role in the pathogenesis of liver fibrosis and may represent an effective therapeutic target in the design of antifibrotic strategies for chronic liver diseases. Methods: Intraperitoneal application of a single dose of either tumor necrosis factor (TNF)‐α or interleukin (IL)‐1β in mice led to an enhanced expression of hepatic TIMP‐1 after 4–16 h. Male Sprague–Dawley rats were treated with carbon tetrachloride (CCl₄) in the presence and absence of specific TNF‐α and IL‐1β inhibitors. Results: Real‐time PCR revealed a significant increase of TIMP‐1 mRNA in total rat liver 24 h after CCl₄ injection. Repetitive injection of both, etanercept and anakinra, before and after CCl₄ injection effectively inactivated TNF‐α and IL‐1β. Anticytokine pretreatment reduced the increase of TIMP‐1 expression after a single CCl₄ injection by 50% and 75%, respectively. In contrast to CCl₄‐treated rats with and without TNF‐α blockade, IL‐1β inactivation caused a sevenfold increase in matrix metalloproteinases‐9 mRNA levels. Conclusions: In conclusion, TIMP‐1 expression is up‐regulated in the early phase of toxic liver injury by proinflammatory cytokines such as TNF‐α and IL‐1β in rodents. Pharmacological inactivation of these cytokines significantly reduces TIMP‐1 gene expression. Our data provide a potential new antifibrotic approach.     

Brugia malayi soluble and excretory‐secretory proteins attenuate development of streptozotocin‐induced type 1 diabetes in mice

Understanding the modulation of the host‐immune system by pathogens‐like filarial parasites offers an alternate approach to prevent autoimmune diseases. In this study, we have shown that treatment with filarial proteins prior to or after the clinical onset of streptozotocin‐induced type‐1 diabetes (T1D) can ameliorate the severity of disease in BALB/c mice. Pre‐treatment with Brugia malayi adult soluble (Bm A S) or microfilarial excretory‐secretory (Bm mf ES) or microfilarial soluble (Bm mf S) antigens followed by induction of diabetes led to lowering of fasting blood glucose levels with as many as 57·5–62·5% of mice remaining nondiabetic. These proteins were more effective when they were used to treat the mice with established T1D as 62·5–71·5% of the mice turned to be nondiabetic. Histopathological examination of pancreas of treated mice showed minor inflammatory changes in pancreatic islet cell architecture. The therapeutic effect was found to be associated with the decreased production of cytokines TNF‐α & IFN‐γ and increased production of IL‐10 in the culture supernatants of splenocytes of treated mice. A switch in the production of anti‐insulin antibodies from IgG2a to IgG1 isotype was also seen. Together these results provide a proof towards utilizing the filarial derived proteins as novel anti‐diabetic therapeutics.     

Melatonin attenuates TNF‐α and IL‐1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

The hormone melatonin has many properties, including antioxidant, anti‐inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose‐dependently inhibits tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐1β expression through the PI3K/AKT, ERK, and NF‐κB signaling pathways. We also identified that melatonin inhibits TNF‐α and IL‐1β production by upregulating miR‐3150a‐3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast‐like synoviocytes confirmed that the MT1 receptor is needed for the anti‐inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen‐induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF‐α and IL‐1β production through downregulation of the PI3K/AKT, ERK, NF‐κB signaling pathways, as well as miR‐3150a‐3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.     

Glycine modulates cytokine secretion,inhibits hepatic damage and improves survival in a model of endotoxemia in mice

Background and aim: There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d ‐galactosamine (d ‐Gal), to modulate pro‐ and anti‐inflammatory cytokine levels, and to improve survival. Methods: Mice were challenged with an intraperitoneal injection of d ‐Gal (16 mg/mouse) and lipopolysaccharide (LPS, 1 μg/mouse). The intervention group also received an intraperitoneal injection of glycine (150 mg/kg) in two doses: 24 h before and just after LPS challenge. Serum cytokine levels were measured 2 h after challenge, and liver enzymes and histology were determined 16 h after LPS. Separate groups of mice received the same treatment and the survival rate was determined 24 h and ten days after endotoxin administration. In in vitro experiments, cultured mononuclear cells were stimulated by LPS, and TNF‐α and IL‐10 secretion were measured, in the presence or absence of glycine. Results: In the glycine‐treated mice, the serum levels of liver enzymes and TNF‐α, the histologic necroinflammation score and the mortality rate were significantly reduced compared to control mice (P<0.001). Serum IL‐10 levels in the glycine‐treated mice were increased (P<0.01). In vitro studies in cultured lymphocytes isolated from either normal or glycine pretreated mice, demonstrated a significant and dose‐dependent inhibition of LPS‐induced TNF‐α secretion and increase in IL‐10 response after treatment with glycine (P<0.01). In conclusion, glycine reduces hepatic damage and improves survival rate in this mouse model of endotoxemia. The protective effect of glycine is associated with modulation of TNF‐α and IL‐10 secretion.     

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β‐cells glucose‐dependently. GIP and GLP‐1 undergo degradation by dipeptidyl peptidase‐4 (DPP‐4), and rapidly lose their biological activities. The actions of GIP and GLP‐1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which are expressed in pancreatic β‐cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP‐1R, as well as mice lacking DPP‐4, showed involvement of GIP and GLP‐1 in divergent biological activities, some of which could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes‐related comorbidity (e.g., obesity, non‐alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin‐based drugs, such as GLP‐1 receptor agonists, which stably activate GLP‐1R signaling, and DPP‐4 inhibitors, which enhance both GLP‐1R and GIPR signaling, showed that GLP‐1 and GIP exert effects possibly linked to prevention or treatment of diabetes‐related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP‐1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes‐related complications and comorbidities.     

Parasite excretory–secretory proteins elicit TRIF dependent CXCL1 and IL‐6 mediated allergic inflammation

Currently, little information is available regarding innate immunity to helminthic parasite infection. In this study, we isolated the excretory–secretory (ES) proteins from Anisakis simplex (sea mammal intestinal parasite) third stage larva. We determined that the levels of IL‐17 in the lung and lung draining lymph node of mice were increased sixfold as a result of intranasal treatment with ES proteins. The ES protein treatment elicited pro‐inflammatory cytokine and chemokine secretion (especially IL‐6 and CXCL1) from mouse lung epithelial cell line and primary lung epithelial cells. In addition, the expression of IL‐6 and CXCL1 in mouse embryonic fibroblast (MEF) cells was significantly increased by the ES protein treatment, but we did not detect these effects in the TRIF^?/? MEF cells. These elevations of IL‐6 and CXCL1 expression were also not diminished by RNase treatment. In conclusion, the ES proteins of helminthic parasite larva may elicit TRIF dependent pro‐inflammatory cytokines, and this is not double‐stranded RNA.     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Combination treatment with alogliptin and voglibose increases active GLP‐1 circulation,prevents the development of diabetes and preserves pancreatic beta‐cells in prediabetic db/db mice

Aim: Alogliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, and voglibose, an alpha‐glucosidase inhibitor, have different but complementary mechanisms of action on glucagon‐like peptide‐1 (GLP‐1) regulation and glucose‐lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice. Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice. Results: After 3 weeks, voglibose treatment increased GLP‐1 secretion (voglibose alone, 1.6‐fold; alogliptin plus voglibose, 1.5‐fold), while it decreased plasma glucose‐dependent insulinotropic polypeptide (GIP) (voglibose alone, ?30%; alogliptin plus voglibose, ?29%). Alogliptin, voglibose and combination treatment decreased plasma DPP‐4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP‐1 levels by 4.5‐, 1.8‐ and synergistically by 9.1‐fold respectively. Combination treatment increased plasma insulin by 3.6‐fold (alogliptin alone, 1.3‐fold; voglibose alone, 1.8‐fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6‐, 3.4‐ and synergistically by 8.5‐fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha‐cell distribution in the pancreatic islet. Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP‐1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta‐cells and islet structure in prediabetic db/db mice.     

IL‐28B (IFN‐λ3) and IFN‐α synergistically inhibit HCV replication

Genetic variation in the IL‐28B (interleukin‐28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon‐α and ribavirin. However, the mechanisms by which polymorphisms in the IL‐28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN‐λs and IFN‐α on HCV RNA replication. The anti‐HCV effect of IFN‐λ3 and IFN‐α in combination was also assessed. Changes in gene expression induced by IFN‐λ3 and IFN‐α were compared using cDNA microarray analysis. IFN‐λs at concentrations of 1 ng/mL or more exhibited concentration‐ and time‐dependent HCV inhibition. In combination, IFN‐λ3 and IFN‐α had a synergistic anti‐HCV effect; however , no synergistic enhancement was observed for interferon‐stimulated response element (ISRE) activity or upregulation of interferon ‐ stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN‐λ3‐induced gene expression occurred later and lasted longer than that induced by IFN‐α. In addition, although the genes upregulated by IFN‐α and IFN‐λ3 were similar to microarray analysis, interferon‐stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN‐α and IFN‐λ3 in combination showed synergistic anti‐HCV activity in vitro. Differences in time‐dependent upregulation of these genes might contribute to the synergistic antiviral activity.     

Glucose‐dependent insulinotropic polypeptide signaling in pancreatic β‐cells and adipocytes

Glucose‐dependent insulinotropic polypeptide (GIP) was the first incretin to be identified. In addition to stimulating insulin secretion, GIP plays regulatory roles in the maintenance, growth and survival of pancreatic islets, as well as impacting on adipocyte function. The current review focuses on the intracellular signaling pathways by which GIP contributes to the regulation of β‐cell secretion and survival, and adipocyte differentiation and lipogenesis. Studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagon‐like peptide‐1. They have provided evidence for contributions by both protein kinase A (PKA) and exchange protein directly activated by cyclic adenosine monophosphate (EPAC2), and their probable role in GIP signaling is discussed. Recent studies have shown that inhibition of the kinase apoptosis signal‐regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria‐induced apoptosis in β‐cells through protein kinase B (PKB)‐mediated pathways, and that GIP‐induced post‐translational modification of voltage‐ dependent K⁺ (Kv) channels also contributes to its prosurvival role. Through regulation of gene expression, GIP tips the balance between pro‐ and anti‐apoptotic members of the B‐cell lymphoma‐2 (Bcl‐2) protein family towards β‐cell survival. GIP also plays important roles in the differentiation of pre‐adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis. These events involve interactions between GIP, insulin and resistin signaling pathways. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00196.x, 2012)     

Trichomonas vaginalis exosome‐like vesicles modify the cytokine profile and reduce inflammation in parasite‐infected mice

Trichomonas vaginalis (Tv) is a flagellated parasite commonly spread through sexual transmission. This protozoan initiates a severe inflammatory process, inducing nitric oxide, interleukin‐6 (IL‐6), IL‐8, IL‐10, IL‐17 and IL‐22 production by host immune cells. The parasites elicit these responses by releasing surface lipophosphoglycan, small extracellular vesicles (exosomes) and other factors. Tv exosomes are similar to mammalian exosomes and have been implicated in the modulation of IL‐8 secretion by epithelial cells. Here, we report that exosome‐like vesicles from T. vaginalis (Tv‐ELVs) induced a more than 15‐fold increase in IL‐10 expression in RAW264.7 macrophages but only a two fold increase in IL‐6 and TNF‐α expression levels measured by RT‐PCR. Because Tv‐ELVs modulated the macrophage response, we also explored the effect of Tv‐ELVs in a murine model of infection. Pretreatment with Tv‐ELVs significantly increased IL‐10 production as measured in vaginal washes by days 8 and 16 post‐infection. Remarkably, Tv‐ELVs‐pretreated mice exhibited a decrease in IL‐17 production and a significant decrease in vulvar inflammation. In addition, IL‐6 and IL‐13 were decreased during infection. Our results suggest that Tv‐ELVs have an immunomodulatory role on the cytokine profile induced by the parasite and promote a decrease in the inflammatory process in mice infected with T. vaginalis.     

Ingestion of a moderate high‐sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon‐like peptide‐1 secretion

Aims/Introduction: Excessive intake of sucrose can cause severe health issues, such as diabetes mellitus. In animal studies, consumption of a high‐sucrose diet (SUC) has been shown to cause obesity, insulin resistance and glucose intolerance. However, several in vivo experiments have been carried out using diets with much higher sucrose contents (50–70% of the total calories) than are typically ingested by humans. In the present study, we examined the effects of a moderate SUC on glucose metabolism and the underlying mechanism. Materials and Methods: C57BL/6J mice received a SUC (38.5% sucrose), a high‐starch diet (ST) or a control diet for 5 weeks. We assessed glucose tolerance, incretin secretion and liver glucose metabolism. Results: An oral glucose tolerance test (OGTT) showed that plasma glucose levels in the early phase were significantly higher in SUC‐fed mice than in ST‐fed or control mice, with no change in plasma insulin levels at any stage. SUC‐fed mice showed a significant improvement in insulin sensitivity. Glucagon‐like peptide‐1 (GLP‐1) secretion 15 min after oral glucose administration was significantly lower in SUC‐fed mice than in ST‐fed or control mice. Hepatic glucokinase (GCK) activity was significantly reduced in SUC‐fed mice. During the OGTT, the accumulation of glycogen in the liver was suppressed in SUC‐fed mice in a time‐dependent manner. Conclusions: These results indicate that mice that consume a moderate SUC show glucose intolerance with a reduction in hepatic GCK activity and impairment in GLP‐1 secretion. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00208.x , 2012)     

Dexamethasone attenuates lipopolysaccharide-induced liver injury by downregulating glucocorticoid-induced tumor necrosis factor receptor ligand in Kupffer cells

Aim: Glucocorticoid‐induced tumor necrosis factor receptor ligand (GITRL) plays pro‐inflammatory roles in immune response. Thus, our aim was to assess if dexamethasone attenuates lipopolysaccharide (LPS)‐induced liver injury by affecting GITRL in Kupffer cells (KC). Methods: A BALB/c mouse model of liver injury was established by i.p. injecting with LPS (10 mg/kg) co‐treated with or without dexamethasone (3 mg/kg). Blood and liver samples were obtained for analysis of liver morphology, GITRL expression, hepatocellular function and cytokine levels at 24 h after injection. KC were isolated and challenged by LPS (1 µg/mL), with or without dexamethasone (10 µM) co‐treatment, or with GITRL siRNA pre‐transfection. The GITRL expression and cytokine levels were assayed at 24 h after challenge. Results: Dexamethasone treatment significantly improved the survival rate of endotoxemic mice (P < 0.05), whereas serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)‐α, interleukin (IL)‐6 and γ‐interferon levels were significantly decreased (P < 0.05, respectively). Concurrently, LPS‐induced hepatic tissue injury was attenuated as indicated by morphological analysis; and expression of GITRL in liver tissue and KC was downregulated (P < 0.05). Consistent with these in vivo experiments, inhibited expression of GITRL, TNF‐α and IL‐6 caused by dexamethasone treatment were also observed in LPS‐stimulated KC. The GITRL, TNF‐α and IL‐6 expression was also significantly inhibited by GITRL gene silencing. Conclusion: The TNF‐α and IL‐6 expression of LPS‐stimulated KC was inhibited by GITRL gene silencing. Dexamethasone attenuates LPS‐induced liver injury, at least proportionately, by downregulating GITRL in KC.