Tryptophan metabolism in atherosclerosis and diabetes

2021 ◽  
Vol 28 ◽  
Author(s):  
Emina Sudar-Milovanovic ◽  
Zoran Gluvic ◽  
Milan Obradovic ◽  
Bozidarka Zaric ◽  
Esma R. Isenovic
Keyword(s):  
Degradation Products ◽  
Treatment Options ◽  
Strong Relationship ◽  
Serum Levels ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Biologically Active ◽  
Low Grade ◽  
Active Metabolites ◽  
Ifn Γ

: The essential amino acid tryptophan (Trp) undergoes catabolism through several pathways, producing biologically active metabolites that significantly impact physiological processes. The metabolic pathway responsible for the majority of Trp catabolism is the kynurenine synthesis pathway (KP). Serotonin and melatonin are among the most essential Trp pathways degradation products. It has emerged that a strong relationship exists between alterations in Trp metabolism and the onset and progression of atherosclerosis and diabetes. Atherosclerosis is a chronic inflammatory disease of the small and medium arteries wall caused by maladaptive local immune responses, which underpins several cardiovascular diseases (CVD). Systemic low-grade immune-mediated inflammation is implicated in atherosclerosis where pro-inflammatory cytokines, such as interferon-γ (IFN-γ), play a significant role. IFN-γ upregulates the enzyme indoleamine 2,3-dioxygenase (IDO), decreasing serum levels of the Trp and increasing metabolite levels of kynurenine. Increased IDO expression and activity could accelerate the atherosclerosis process. Therefore, activated IDO inhibition could offer possible treatment options regarding atherosclerosis management. Diabetes is a chronic metabolic disease characterized by hyperglycemia that, over time, leads to severe damage to the heart, blood vessels, eyes, kidneys, and peripheral nerves. Trp serum levels and lower activity of IDO were higher in future type 2 diabetes (T2DM) patients. This article reviews recent findings on the link between mammalian Trp metabolism and its role in atherosclerosis and diabetes and outlines the intervention strategies.

scholarly journals Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice

2020 ◽  
Vol 34 ◽  
pp. 205873842092944
Author(s):  
Chieh-Shan Wu ◽  
Shih-Chao Lin ◽  
Shiming Li ◽  
Yu-Chih Chiang ◽  
Nicole Bracci ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Levels ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Mitogen Activated Protein Kinase ◽  
Normal Ranges ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Allergic Contact

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient’s quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4+ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.

High Serum Levels of CXCL11 in Mixed Cryoglobulinemia Are Associated with Increased Circulating Levels of Interferon-γ

2011 ◽  
Vol 38 (9) ◽  
pp. 1947-1952 ◽  
Author(s):  
ALESSANDRO ANTONELLI ◽  
CLODOVEO FERRI ◽  
SILVIA MARTINA FERRARI ◽  
ILARIA RUFFILLI ◽  
MICHELE COLACI ◽  
...  
Keyword(s):  
Strong Relationship ◽  
Serum Levels ◽  
Mixed Cryoglobulinemia ◽  
Interferon Γ ◽  
High Serum ◽  
Hepatitis C Infection ◽  
T Helper 1 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α

Objective.No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with “mixed cryoglobulinemia and chronic hepatitis C infection” (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.Methods.Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.Results.MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8–114.5), 1.4 (range 0.7–2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8–369), 1.1 (range 0.7–3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).Conclusion.Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.

Inflammatory, cardio-metabolic and diabetic profiling of chronic schizophrenia

2017 ◽  
Vol 39 ◽  
pp. 1-10 ◽  
Author(s):  
R. Balõtšev ◽  
K. Koido ◽  
V. Vasar ◽  
S. Janno ◽  
K. Kriisa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chronic Schizophrenia ◽  
Interferon Γ ◽  
Low Grade ◽  
Serum Samples ◽  
Clinical Biomarkers ◽  
Tnf Α ◽  
Ifn Γ

AbstractBackgroundThere is a growing interest in low-grade inflammatory and metabolic alterations in patients with chronic schizophrenia (SCH).MethodsInflammatory (tumor-necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukins [IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10], monocyte chemo-attractant protein-1 [MCP-1]) and growth factors (vascular endothelial growth factor [VEGF], epidermal growth factor [EGF]) were measured in blood serum samples of 105 SCH patients and 148 control subjects (CS). Simultaneously the clinical biomarkers (C-reactive protein [CRP], triglycerides [TG], low-density lipoprotein [LDL-c] and high-density lipoprotein [HDL-c] cholesterol, glycated hemoglobin [HbA1c]) were measured, and body mass index (BMI) was calculated for patients.ResultsSeveral cyto-/chemokines (IFN-γ, MCP-1, IL-2, IL-6, IL-8 and IL-10) were significantly (P < 0.0000001) elevated in SCH patients compared to CS. Odds ratios, obtained from logistic regression analyses, were significantly elevated for IL-2, IL-6, IL-10, INF-γ, and decreased for TNF-α in SCH group. Among the patients, higher IL-2, IL-6, INF-γ and lower MCP-1 levels as well as male gender were together significant (P < 0.000001) predictors of higher HbA1c levels, and TG/HDL-c parameter was associated with ratios of INF-γ/IL-10 (P = 0.004), and INF-γ/IL-4 (P = 0.049), HbA1c (P = 0.005), INF-γ (P = 0.009), as well as LDL-c (P = 0.02) levels.ConclusionsIL-2, IL-6, IL-10 and IFN-γ were the most significant SCH-related markers among the measured cytokines in our patient group. Furthermore, significant associations between pro-/anti-inflammatory imbalance and HbA1c as well as cardio-metabolic risk marker (TG/HDL-c) were observed, indicating higher risks of diabetes and cardiovascular diseases among SCH patients.

Effects of the Japanese herbal medicine ‘Inchinko-to’ (TJ-135) on concanavalin A-induced hepatitis in mice

2000 ◽  
Vol 99 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Masayoshi YAMASHIKI ◽  
Akihito MASE ◽  
Ichiro ARAI ◽  
Xian-Xi HUANG ◽  
Tsutomu NOBORI ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Concanavalin A ◽  
Serum Levels ◽  
Interferon Γ ◽  
Hepatic Necrosis ◽  
Interleukin 12 ◽  
Con A ◽  
Ifn Γ

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-γ (IFN-γ) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-γ was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.

scholarly journals CXCL9: a biomarker for the coronary slow flow phenomenon in patients with coronary artery disease

2019 ◽  
Author(s):  
youfeng Liang ◽  
xianhe Lin ◽  
yuanyuan Xu ◽  
chunmiao Wang ◽  
Qi Zhou
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Inflammatory Responses ◽  
Multivariate Logistic Regression Analysis ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Chronic Inflammatory Disease ◽  
Timi Frame Count ◽  
Ifn Γ ◽  
Artery Disease

Abstract Background: Atherosclerosis is a chronic inflammatory disease. The pathology underlying the disease consists of accumulation of the extracellular matrix, lipid and inflammatory cells. Coronary s low f low p henomenon (CSFP) is closely related to inflammatory responses, while chemokines plays an important role in the progression of atherosclerosis. However, the relationship between chemokines and CSFP is still unclear. In this study, our aims were to evaluate the association between CXC Chemokines 9 (CXCL9) levels and CSFP in patients with coronary artery disease. Methods: We studied 46 patients diagnosed with CSFP and classifyed them as the CSFP group. 50 patients with normal coronary angiography (CAG) were randomly selected as the no-CSFP group in our study. The mean TIMI frame count (TFC) was used to measure coronary blood flow velocity. The clinical and biochemical index, including serum levels of IL1, IL-6, IL-10, CXCL9, CD40L and interferon- γ (IFN- γ ), were analyzed in all subjects. Results: The serum levels of IL-1, IL-6, IL-10, CXCL9, CD40L, IFN- γ and CXCL9 in the CSFP group were significantly higher than those in the no-CSFP group, with the differences being statistically significant (p<0.001). Furthermore, Pearson's correlation analysis reflected a significant positive correlation (r=0.171, p=0.01) in CXCL9 levels. Multivariate logistic regression analysis showed that CXCL9 is an important risk factor for CSFP ( β =1.795, P =0.000). Subsequent ROC curve analyses indicated that the serum CXCL9 levels demonstrated a high diagnostic value in differentiating patients with CSFP from that of normal controls (Area Under the Curve = 0.758) and the serum CXCL9 level of 131.915 mg/L was a predictor of CSFP, with a sensitivity of 54 . 3 % and a specificity of 96.0%, respectively. Conclusions: Our findings are indicative of the potential clinical implications of CXCL9 in the occurrence and development of CSFP.

scholarly journals Expression of Cd28 and Cd86 by Human Eosinophils and Role in the Secretion of Type 1 Cytokines (Interleukin 2 and Interferon γ)

1999 ◽  
Vol 190 (4) ◽  
pp. 487-496 ◽  
Author(s):  
Gaëtane Woerly ◽  
Nadine Roger ◽  
Sylvie Loiseau ◽  
David Dombrowicz ◽  
André Capron ◽  
...  
Keyword(s):  
Costimulatory Molecule ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Biologically Active ◽  
Immunoregulatory Cytokines ◽  
Type 2 Cytokines ◽  
Ifn Γ ◽  
Blood Eosinophils

Eosinophils are the source of various immunoregulatory cytokines, but the membrane molecules involved in their secretion have not been clearly identified. Here we show that peripheral blood eosinophils from hypereosinophilic patients could express membrane CD86 but not CD80. The T cell costimulatory molecule CD28 is also detected on the eosinophil surface. CD28 ligation but not CD86 ligation resulted in interleukin (IL)-2 and interferon (IFN)-γ secretion by eosinophils, whereas IL-4, IL-5, and IL-10 were not detected. In contrast to T cells requiring two signals for effective stimulation, CD28 ligation alone was sufficient for optimal eosinophil activation. Eosinophil-derived IL-2 and IFN-γ were biologically active, as supernatants from anti-CD28–treated cells were able to induce CTLL-2 proliferation and major histocompatibility complex class II expression on the colon carcinoma cell line Colo 205, respectively. Addition of secretory immunoglobulin (Ig)A–anti-IgA complexes, which could induce the release of IL-10, very significantly inhibited both CD28-mediated IL-2 and IFN-γ release. These results suggest that the release of type 1 (IFN-γ and IL-2) versus type 2 cytokines by eosinophils is not only differential but also dependent on cross-regulatory signals. They confirm that through activation of costimulatory molecules, eosinophils could function as an immunoregulatory cell involved in the release of both type 1 and type 2 cytokines.

scholarly journals Cytokine Involvement in Immunomodulatory Activity Affected by Candida albicans Mannan

1998 ◽  
Vol 66 (4) ◽  
pp. 1384-1391 ◽  
Author(s):  
Yanyun Wang ◽  
Shaokang P. Li ◽  
Stephen A. Moser ◽  
Kenneth L. Bost ◽  
Judith E. Domer
Keyword(s):  
Candida Albicans ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Biologically Active ◽  
Enzyme Linked Immunosorbent Assay ◽  
Murine Splenocytes ◽  
Effector Cells ◽  
Ifn Γ ◽  
In Vivo Administration

ABSTRACT Candida albicans mannoprotein (MAN) administered intravenously to mice stimulates the production of splenic CD8+ effector cells which downregulate delayed hypersensitivity (DH) in immunized mice. Cytokine involvement in the induction and/or elicitation of downregulation was studied by (i) examining murine splenocytes qualitatively for mRNA for interleukin-2 (IL-2), IL-4, IL-10, IL-12p40, and gamma interferon (IFN-γ), (ii) quantitating splenocyte mRNA for IL-12p40 by quantitative-competitive reverse transcriptase-mediated PCR, and (iii) measuring serum levels of IL-12p40 and IL-12p70 by capture enzyme-linked immunosorbent assay, each performed at selected intervals over 96 h after giving MAN. Further, the effect of in vivo administration of anti-IL-4 on the induction and elicitation of MAN-specific DH in MAN-treated mice was measured. Expression of IL-12p40 mRNA in the spleen was reduced to near 0 during the first 24 h but rebounded thereafter. Transcripts for IL-10 were present throughout the 96-h period, whereas those for IL-4 and IFN-γ were either weak or undetectable prior to 24 to 48 h. In vivo administration of anti-IL-4 partially abrogated the downregulatory effect of MAN only when given at the time of MAN administration. Serum levels of IL-12p40, but not IL-12p70, were increased by 24 h and maximal at 48 h. The antagonistic effect of IL-12p40 could contribute to the mechanism(s) for downregulation of DH. Moreover, IL-10, IL-4, and/or IFN-γ, interacting with MAN-activated cells in the absence of biologically active IL-12, may induce the production of CD8+ downregulatory effector cells. Partial abrogation of downregulatory activity in animals treated with anti-IL-4 at the time of induction of such activity lends support to this hypothesis.

scholarly journals Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

2018 ◽  
Vol 21 (1s) ◽  
pp. 117s-129s ◽  
Author(s):  
Navaz Karimian Pour ◽  
Micheline Piquette-Miller
Keyword(s):  
Mrna Expression ◽  
Bacterial Infections ◽  
Drug Transporters ◽  
Serum Levels ◽  
Low Grade ◽  
Western Blots ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Associated Conditions ◽  
Ifn Γ

PURPUSE: Bacterial co-infections and low grade endotoxemia are common in HIV patients. Inflammation due to endotoxin or HIV may influence the expression and activity of transporters. Kidney transporters influence renal drug clearances including many antiretroviral agents. Our objective was to study the effect of endotoxin and HIV on the renal expression of drug transporters in an HIV-transgenic (HIV-Tg) rat model. These rats develop immune dysfunction and AIDS-associated conditions like humans. METHODS: Endotoxin or saline was administered intraperitoneally to HIV-Tg or wild type (WT) littermates and kidneys were collected 18 hours later. Expression of transporters and cytokines were measured by qRT-PCR and Western blots. Serum cytokine levels were measured by ELISA. RESULTS: Endotoxin induced serum levels of IL-6, TNF-α and IFN-γ in both HIV-Tg and WT animals. The basal mRNA expression of Oct2, Oct3, Octn1, Mate1, Urat1 and Ent1was significantly lower (33-60%) and the expression of Ent2 and Pept2 was significantly higher (33-45%) in HIV-Tg as compared to WT. While endotoxin significantly downregulated the mRNA expression of Mdra1 and Pept2 in both HIV and WT groups (69-78%), it imposed a significant reduction on the mRNA expression of Oct2, Oct3, Octn1, Mate1, Oat2, urat1, and Ent1 (54-83%) only in the WT group. Endotoxin significantly increased the mRNA expression of Pept1 (140%) in both WT and HIV groups. CONCLUSIONS: HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters although co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates in patients and could potentially be a source of drug-disease interactions.

scholarly journals Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans

2014 ◽  
Vol 307 (7) ◽  
pp. G673-G688 ◽  
Author(s):  
Kacper A. Wojtal ◽  
Alexandra Cee ◽  
Silvia Lang ◽  
Oliver Götze ◽  
Heiko Frühauf ◽  
...  
Keyword(s):  
High Altitude ◽  
Serum Levels ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Matrix Metalloproteinase 2 ◽  
Mrna Levels ◽  
Active Compounds ◽  
Slc Transporters ◽  
Ifn Γ

Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals ( n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans.

Glucan phosphate potentiates endotoxin-induced interferon-γ expression in immunocompetent mice, but attenuates induction of endotoxin tolerance

2001 ◽  
Vol 101 (6) ◽  
pp. 541-550 ◽  
Author(s):  
Edward R. SHERWOOD ◽  
Tushar K. VARMA ◽  
Ricki Y. FRAM ◽  
Cheng Y. LIN ◽  
Aristides P. KOUTROUVELIS ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Serum Levels ◽  
Severe Trauma ◽  
Interferon Γ ◽  
Experimental Models ◽  
Interleukin 12 ◽  
Induction Phase ◽  
Ifn Γ ◽  
Antimicrobial Immunity ◽  
Marked Suppression

Glucan phosphate has been shown to enhance antimicrobial immunity in a variety of experimental models. However, the mechanisms by which glucans enhance resistance to infection remain largely unknown. Interferon-γ (IFN-γ) is a key regulator of both innate and acquired immunity. Suppression of IFN-γ production is a prominent feature of the altered immune response that follows major trauma or sepsis. The present studies were designed to determine the effect of glucan phosphate on IFN-γ expression in normal mice and endotoxin [lipopolysaccharide (LPS)]-tolerant mice. The model of LPS tolerance was used because it results in patterns of cytokine expression similar to those commonly observed following severe trauma or sepsis. Glucan treatment potentiated LPS-induced IFN-γ expression in control mice. The induction of LPS tolerance resulted in marked suppression of LPS-induced IFN-γ production. However, co-administration of glucan with LPS, during the tolerance induction phase, attenuated the LPS-tolerant response. Interleukin-12 (IL-12) and IL-18 are important mediators of LPS-induced IFN-γ production. LPS-induced IL-12 p40 mRNA expression was increased in the spleens of glucan-treated mice compared with controls. Induction of LPS tolerance caused marked suppression of IL-12 production, a response that was attenuated by glucan treatment. IL-18 was constitutively expressed in both control and LPS-tolerant mice, and LPS-induced serum levels of IL-18 were increased in mice treated with glucan. T cells isolated from glucan-treated mice exhibited increased IFN-γ expression in response to IL-12 and IL-18, as well as increased expression of the IL-12 and IL-18 receptors. The ability of glucan to potentiate IFN-γ expression in control mice provides a potential mechanism by which glucan enhances antimicrobial immunity. The ability of glucan to attenuate suppressed IFN-γ expression in LPS-tolerant mice denotes its potential benefit for the treatment of trauma and sepsis-induced immunosuppression.

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