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To explore the effect of Maxing Shigan decoction on serum Toll like receptor (TLR) 2, TLR4, and helper T cell (Th) 1/Th2 immune balance in children with mycoplasma pneumoniae pneumonia (MPP) of wind heat closed lung syndrome. 100 children with MPP who were admitted to Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine from January 2021 to January 2023 were divided into combined group (treated with conventional western medicine combined with Maxing Shigan decoction, 50 cases) and control group (treated with conventional western medicine, 50 cases) according to the random number table method. The changes in traditional Chinese medicine syndrome scores, tidal breathing and lung function indicators, TLR2, TLR4, and Th1/Th2 immune balance indicators between two groups were compared. 14 d after treatment, the scores of fever and aversion to wind, slight sweating, cough, thirsty and eager to drink, tachypnea, phlegm thick and yellow in color, pharyngeal redness in combined group were lower than those in control group (P<0.05). 14 d after treatment, the tidal volume (TV), inspiratory time to expiratory time ratio(I/E), and the expiratory volume at peak tidal expiratory flow and total expiratory volume ratio (VPEF/VE) in combined group were higher than those in control group, and respiratory rate(RR) was lower than that in control group (P<0.05). 14 d after treatment, the TLR2 and TLR4 in combined group were lower than those in control group (P<0.05). 14 d after treatment, the interferon γ (IFN-γ) and IFN-γ/interleukin-4 (IL-4) in combined group were lower than those in control group, and IL-4 was higher than that in control group (P<0.05). Maxing Shigan decoction in the treatment in children with MPP of wind heat closed lung syndrome, which can promote the improvement of clinical symptoms, which can also improve lung function and immune function in children at the same time, regulate the serum TLR2, TLR4 levels. [ABSTRACT FROM AUTHOR]

A furuncle is an infection of the skin and subcutaneous tissue that involves hair follicles and ultimately results in the formation of an abscess. Furunculosis is most frequently caused by Staphylococcus aureus. interleukin-33, human β defensin 2, and Toll-like receptor 2 (Toll like receptor 2) play a significant role in the innate immunity of the host. The present study aims to determine the level of the interleukin-33, human β defensin 2, and Toll like receptor 2 gene expression in staphylococcal furunculosis. A case-control study includes 50 patients and 50 control were evaluated for the level of interleukin 33, human β defensin and Toll like receptor 2 by enzyme and qPCR, respectively. The results indicated that furunculosis was most prevalent in people between the ages of 25 and 45 (P > 0.05). However, there was no significant difference between males and females (P > 0.05). The serum levels of interleukin-33 were observed to be significantly higher in FP compared to HC. Toll like receptor 2 and human β defensin 2 were elevated in PF, but much more in female patients than in male patients (P < 0.05). In conclusion, the findings of the present study reveal that it is more likely that Toll like receptor 2, human β defensin 2, and interleukin-33 play a significant role in the host's defense against S. aureus infection. [ABSTRACT FROM AUTHOR]

Aims: Bronchial asthma is a life-threatening disease with a multifactorial etiology. It was shown that immunological dysregulations play an essential role in the exacerbation of the patient's attacks. Tolllike receptors act as a bridge in the transmission of different signals associated with the regulation of immune responses. According to numerous research, TLR2 causes different outcomes in asthma. TLR2 and TLR4 overexpression seems to predispose to an increase in the frequency of dyspneic attacks. Therefore, this study aimed to learn more about the function of TLR2 and TLR4 and investigate their underlying association with allergic airway inflammation in asthmatic patients. Malerials & Methods: In this case-control study conducted at outpatient clinics in a Specialized Allergy Center in Basrah City, South of Iraq, 70 asthmatic patients and 70 healthy individuals were investigated. 4ml of venous blood was drawn and divided into two parts: 2ml was used for RNA extraction and qRT-PCR, and another 2ml was used for the serological tests. Data analysis was done by SPSS 26 software. Findings: The mean serum levels of TLR2 and TLR4 were significantly higher in the asthmatic group (28.33±13.00ng/ml and 46.30±20.32ng/ml, respectively) than in the control group (7.33±3.73ng/ml and 26.28±14.32ng/ml, respectively). Also, the expression level of TLR2 and TLR4 was significantly higher in the asthmatic group (p<0.05). Conclusion: TLR2 and TLR4 are increased in patients with bronchial asthma compared to healthy individuals. Elevated levels of both biomarkers may act as a trigger for increased secretion of other cytokines, leading to exacerbation of asthmatic signs and symptoms. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We evaluated the effects of probiotic supplementation with a low-calorie diet on the gene expression of mediators of the immune system among overweight and obese individuals; participants were randomly divided into three groups of 25 each: group 1 consumed conventional yogurt with a low-calorie diet (CLCD); group 2 consumed probiotic yogurt with a low-calorie diet (PLCD) and group 3 consumed probiotic yogurt without a low-calorie diet (PWLCD) for 8 weeks. Probiotic yogurt contained Lactobacillus acidophilus LA5, Lactobacillus casei DN001, Bifidobacterium lactis Bb12 and Streptococcus thermophiles (108 CFU/mL each). Quantitative results of RT-PCR demonstrated that there was an increase in the gene expression of toll like receptor 2(TLR2) in PLCD group compared to CLCD and PWLCD groups (2.7 ± 2.8 vs. 0.9 ± 0.8, 1.9 ± 1.6, respectively, P = 0.001) as well as an increase in FOXP3 gene in PLCD group compared to the other groups (11.2 ± 6.7 vs. 6 ± 2.5, 6.3 ± 1.9, respectively, P

Host defense against infectious disease is a tormenting task considering not only the enormous pathogens diversity, but also their rapid genome replication and mutation rates. Front line and anti-microbial defense is accomplished by the innate immune system with the help of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) in prompt pathogens detection. In this study, distribution of single nucleotide polymorphisms (SNPs) in TLR2 gene was studied in two cattle breeds Dhanni and locally adapted exotic Jersey. The complete sequences of TLR2 gene composed of 5'UTR 136 bp, coding sequence 2355 bp and 3'UTR 1316 bp. Phylogenetic analysis revealed clustering of Dhanni with Bos indicus and Jersey with Bos taurus as the nearest neighbor. Sequencing of TLR2 in Dhanni cattle showed the occurrence of 35 variable sites within coding region including 37% non-synonymous and 63% synonymous, while in Jersey cattle, 21 SNPs were identified within coding region including 48% non-synonymous and 52% synonymous. Mostly SNPs fell within the leucine-rich repeats (LRR) of extracellular domain, regions responsible for ligand recognition. The ratio of dS/dN substitutions was <1 at polymorphic-sites indicating purifying selection. The SNPs at position 681 (p.Leu227Phe in Jersey) and 521(p.Thr174Ile in Dhanni) were presumed to have possible damaging or functional altering effect. The predicted bovine TLR2 is a solenoid-like (coil-like) built from 20 LRRs bend into a horseshoe shaped structure. The polymorphisms in TLR2 can be useful in future research exploring its role in immunity and may be used as markers for disease resistance under selective breeding. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys­tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), β-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review.

Cutaneous leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous leishmaniasis.

Reducing inflammation is a promising approach for the prevention and treatment of septic acute kidney injury (AKI), since AKI is characterized by excessive inflammation in the kidney. Previous studies have demonstrated that toll-like receptor 2 (TLR2) is overstimulated, which promotes inflammation by activating the NF-κB signaling pathway, in a lipopolysaccharide (LPS)-induced model of AKI mice. For the present study, it was hypothesized that TLR2 inhibition could reduce inflammation and consequently prevent septic AKI. Therefore, the potential renal protective effects of ortho-vanillin (OV), an inhibitor of TLR2, were investigated in the present study in vitro and in vivo. In vitro treatment with OV on LPS-stimulated mouse podocyte cell line MPC5 did not affect TLR2 expression but interrupted the interaction between TLR2 and its downstream adaptor MyD88, resulting in the reduction of inflammatory cytokines IL-6 and TNF-α expression. In vivo OV treatment in an LPS-challenged mouse model effectively alleviated LPS-induced kidney injury as indicated by histology analysis and the significantly reduced blood urea nitrogen and serum creatinine levels. Additionally, inflammatory cytokines TNF-α, IL-6 and IL-1β expression were also significantly reduced in mice with OV treatment. Signaling pathway analysis further demonstrated that OV treatment did not affect the expression of TLR2 and p65 but suppressed p65 phosphorylation. Taken together, data from the present study demonstrated that OV was effective in protecting renal function against LPS-induced AKI through the inhibition of TLR2/NF-κB signaling and subsequent inflammatory cytokine production. These findings indicated that OV or targeting TLR2 signaling in general, represents a novel therapeutic approach for use in the prevention and treatment of AKI. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous system (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), β-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)- dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a disease of global importance. There is an increasing recognition of the role of Toll like receptors, important pattern recognition receptors of host immune system, in determining the susceptibility or resistance to TB in various populations. In an attempt to examine the importance of Toll like receptors in immune response to Mycobacterium tuberculosis infection, we explored two variants each of TLR2 and TLR9 in a population residing in Uttar Pradesh, India. Genotyping was performed to detect -196 to -174 del polymorphism and G2258A SNP (Arg753Gln, rs5743708) in TLR2 gene and -T1237C (rs5743836) and G2848A (rs352140) SNP in TLR9 gene in patients with pulmonary TB and healthy controls. The A allele of G2848A SNP in TLR9 gene was found with a marginally higher frequency among TB patients as compared to healthy controls, suggesting that A allele at position 2848 of TLR9 gene may be associated with susceptibility to TB in North Indian population [p = 0.05, Mantel-Haenszel OR = 1.34, 95% CI (1.0-1.82)]. [ABSTRACT FROM AUTHOR]

Obesity and diabetes are characterized by low grade chronic inflammation status and insulin resistance in adipose tissue associated with metalloproteinase inhibitor 1 (TIMP1). Interleukin (IL)29, exhibits multiple immune regulatory activities. However, the role of IL29 and its effects on TIMP1 remain to be elucidated. The present study was designed to investigate the effects of IL29 on expression of TIMP1 in macrophages associated with inflammation in adipose tissue. IL29 and high glucose were used to activate Raw264.7 cells and primary macrophages with or without antibody‑mediated inhibition of toll like receptor (TLR) 2 and TLR4. TIMP1 was measured in culture media of Raw264.7 cells and primary macrophages by ELISA. IL29 and high glucose increased TIMP1 levels in Raw264.7 cells and primary macrophages. Antibody‑mediated inhibition of TLR2 or TLR2 gene knockout decreased TIMP1 levels activated by IL29, however not by high glucose in the medium of Raw264.7 cells and primary macrophages. Furthermore, antibody‑mediated inhibition of TLR4 or TLR4 gene knockout decreased TIMP1 levels which were stimulated by high glucose, not by IL29 in the medium of Raw264.7 cells and primary macrophages. The results of the present study indicate that TLR2 is involved in IL29‑stimulated TIMP1 expression in Raw264.7 cells and primary macrophages. [ABSTRACT FROM AUTHOR]

We evaluated the effects of probiotic supplementation with a low-calorie diet on the gene expression of mediators of the immune system among overweight and obese individuals; participants were randomly divided into three groups of 25 each: group 1 consumed conventional yogurt with a low-calorie diet (CLCD); group 2 consumed probiotic yogurt with a low-calorie diet (PLCD) and group 3 consumed probiotic yogurt without a low-calorie diet (PWLCD) for 8 weeks. Probiotic yogurt contained Lactobacillus acidophilus LA5, Lactobacillus casei DN001, Bifidobacterium lactis Bb12 and Streptococcus thermophiles (10 8 CFU/mL each) . Quantitative results of RT-PCR demonstrated that there was an increase in the gene expression of toll like receptor 2(TLR2) in PLCD group compared to CLCD and PWLCD groups (2.7 ± 2.8 vs. 0.9 ± 0.8, 1.9 ± 1.6, respectively, P = 0.001) as well as an increase in FOXP3 gene in PLCD group compared to the other groups (11.2 ± 6.7 vs. 6 ± 2.5, 6.3 ± 1.9, respectively, P < 0.001). Our study demonstrated that the 8-week consumption of PLCD among overweight and obese individuals resulted in a significant up-regulation in the expression of the TLR2. [ABSTRACT FROM AUTHOR]

There are few studies on the role of innate immune response in dermatophytosis. An investigation was conducted to define the involvement of Toll-Like Receptors (TLRs) 2 and 4 in localized (LD) and disseminated (DD) dermatophytosis due to T. rubrum. Fifteen newly diagnosed patients, eight patients with LD and seven with DD, defined by involvement of at least three body segments were used in this study. Controls comprised twenty skin samples from healthy individuals undergoing plastic surgery. TLR2 and TLR4 were quantified in skin lesions by immunohistochemistry. A reduced expression of TLR4 in the lower and upper epidermis of both LD and DD patients was found compared to controls; TLR2 expression was preserved in the upper and lower epidermis of all three groups. As TLR4 signaling induces the production of inflammatory cytokines and neutrophils recruitment, its reduced expression likely contributed to the lack of resolution of the infection and the consequent chronic nature of the dermatophytosis. As TLR2 expression acts to limit the inflammatory process and preserves the epidermal structure, its preserved expression may also contribute to the persistent infection and limited inflammation that are characteristic of dermatophytic infections.

Abstract: Proximal tubule protein take‐up is interceded by 2 receptors, megalin and cubilin. These receptors rescue an assortment of filtered ligands including fundamental vitamins and hormones. The objective of this study was to investigate the potential relation of megalin receptor injury with nuclear factor‐kappa B (NF‐κB) upregulation in acute kidney injury rat model. Twenty four rats were allocated into two groups: control group received saline, while the second group was intoxicated with cadmium chloride (2.4 mg Cd/kg/day i.p) for 30 days. Blood urea nitrogen, serum creatinine, tissue oxidant–antioxidant parameters (malondialdehyde [MDA] and reduced glutathione [GSH]) and expression levels for NF‐κB, toll like receptor‐2 (TLR2), toll like receptor‐4 (TLR4), and megalin receptor were estimated. Noticeable downregulation of megalin receptor versus upregulation of NF‐κB, TLR2, and TLR4 were observed in AKI rat model together with significant elevation in MDA as well as significant reduction in GSH. The study concluded that the oxidative stress in kidney tissue leads to megalin receptor damage, which indeed motivates upregulation of NF‐κB through TLRs 2 and 4 pathways. [ABSTRACT FROM AUTHOR]

The anti-proliferative effect and down regulation of vascular endothelial growth factor C and toll like receptor-2 by kolaviron on Wuchereria bancrofti infected peripheral blood lymphocytes were investigated. Blood were collected from consenting volunteers in Talata Mafara, Nigeria, between the hours of 10 pm to 12 am, and microscopically identified for microfilariae. W. bancrofti positive samples were cultured for 72 h treated with Doxycycline (2 μg/ml) and kolaviron (5 μg/ml) in vitro . Mitotic index, expression of vascular endothelial growth factor-C (VEGF-c), toll like receptor-2 (TLR-2) were determined using standard procedures. Mitotic index was significantly (P < 0.05) reduced in the kolaviron treated group compared to negative control. Kolaviron also significantly (P < 0.05) down regulated the expression of VEGF-c and TLR-2 when compared with the untreated group. In both cases, the effects of kolaviron was not significantly different (P < 0.05) to that of doxycycline. Furthermore, strong positive correlations between mitotic index, VEGF-c and TLR-2 expressions were observed. The study suggests that kolaviron rich portion of Garcinia kola exhibited anti-proliferative effect and down regulation of VEGF-c and TLR-2 in W. bancrofti infected blood. Thus, the results from this study might have unravelled the potency of kolaviron in the management of complications associated with lymphatic filariasis. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4+ T cells and up-regulate T-cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4+ T-cell differentiation and function, we conducted a gene expression analysis of murine naïve CD4+ T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4+ T-cells co-stimulated via TLR2 showed a significant up-regulation of Il9 mRNA compared to cells co-stimulated via CD28. Under TH9 differentiation, we observed up-regulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non-polarizing conditions, TLR2 engagement on CD4+ T-cells had minimal effect on IL-9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN-γ secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4+ T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T-cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva, which is characterized by antigen challenge and toll-like receptor 2 (TLR2) activation. Here, a designed small peptide ZY12 was found to contain therapeutic potential in staphylococcal enterotoxin B (SEB)-induced AC model. ZY12 treatment showed the remission of clinical signs, plasma total IgE levels, number of mast cells and the proportion of degranulated mast cell in AC mice. Levels of Th2 cytokines (IL-4, IL-5, IL-13) in the lymph nodes or spleen were significantly decreased while those of Th1 cytokine (IFN-γ) were increased in ZY12 treated group, suggesting a protective role of ZY12 in AC by mediating the balance of Th1/Th2 cytokines. Importantly, ZY12 significantly inhibited TLR2 expression in conjunctival tissue. Combined its therapeutic effects with TLR2 inhibitory function, ZY12 might be an ideal candidate for the development of new therapeutic agent for allergic disease. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D levels and genetic factors, vitamin D receptor (VDR) and Toll like receptor- 2 (TLR-2) gene single nucleotide polymorphisms (SNPs), determine susceptibility to pulmonary tuberculosis. We aimed to evaluate vitamin D deficiency, VDR and TLR-2 gene SNPs in tuberculous meningitis (TBM). Methods: This case-control study included 130 subjects each in three arms (TBM, pulmonary tuberculosis and healthy control). This study was performed in a large tertiary care institution of North India. Subjects were enrolled from August 2013 to July 2015. Vitamin D levels were measured using enzyme immunoassay. SNPs in VDR and TLR-2 gene were assessed using polymerase chain reaction-sequencing method. TBM patients were followed for 6 months. Results: Vitamin D deficiency was significantly more common in TBM compared to controls and pulmonary tuberculosis (TBM versus controls p < 0.001; TBM versus pulmonary tuberculosis p < 0.001). The heterozygous (TC) and mutant (CC) genotypes of Taq1 VDR SNP were significantly associated with TBM as compared to controls [TC; p < 0.001, odds ratio (OR) = 3.53 (1.95-6.40); CC; p = 0.002 OR = 5.97 (1.89-18.84)]. The heterozygous genotypes were significantly associated with TBM as compared with pulmonary tuberculosis [ p = 0.001; OR = 2.53(1.43-4.45)]. Heterozygous (TG) and mutants (GG) forms of Apa1 VDR SNPs were significantly associated with TBM compared to controls [TG; p = 0.001, OR = 2.86 (1.58-5.17), GG; p = 0.002, OR = 5.11 (1.80-14.54)] and pulmonary tuberculosis. There was no significant difference in the frequency of TLR-2 SNPs. No association was found between outcome of TBM and vitamin D deficiency, VDR or TLR-2 SNPs. Conclusion: Vitamin D deficiency and VDR polymorphisms are associated with the susceptibility of TBM. [ABSTRACT FROM AUTHOR]

Background: Laryngeal carcinoma induce immune system suppression in tumour micro environments with unknown mechanism. Toll like receptors (TLRs) are important molecules which play a critical role in the management and induction of immune responses. In this regard, the importance and the role of TLR 2, 4 and 9 have not been studied together in laryngeal cancer. The present study aims to evaluate the expression level of TLR2, TLR4 and TLR9 in patients with laryngeal carcinoma. Materials and Methods: 89 tumour samples and 35 tumour-free tissues were obtained from laryngeal carcinoma male patients and the expression level of TLR2, TLR4 and TLR9 was analysed using Real-time PCR method. Results: The expression level of TLR2 was increased as the result of increasing lymph node involvement, pretumoral involvement and regional metastasis. Also, the TLR4 gene expression levels were increased 1.5 fold in patients with lymph node involvement. The expression Level of TLR9 was increased by increasing stage and primary tumour involvement. The expression pattern of TLR2 and TLR4 in tumour and tumour-free tissues was the same, while TLR9 gene expressions show higher level in tumour tissues than its normal tissue. None of our findings were statistical significant. Conclusion: we have shown that the expression status of TLR2, TLR4 and TLR9 in patients with laryngeal cancer was correlated with their clinicopathologic features. Additionally, the expression level of TLRs in cancerous and non-cancerous tissues shows no significant changes. [ABSTRACT FROM AUTHOR]

Copyright of Revista do Instituto de Medicina Tropical de São Paulo is the property of Instituto de Medicina Tropical de Sao Paulo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Background: Toll-like receptor 2 (TLR2) molecules play a pivotal role in innate immune responses by their ability to recognize and sense a wide repertoire of infectious and endogenous cellular structural elements. Here we evaluated whether genetic variants in TLR2 influence the age of the disease onset in bipolar disorder (BD). Methods: DNAs from 571 BD patients 229 early-onset (EO-BD) and 342 late-onset (LO-BD) and 199 healthy controls (HC) were analyzed for the following TLR2 polymorphisms: the 5′-UTR −196 to −174 insertion/deletion (ins/del), the intron 1 rs4696480 A/T, and the exon 3 rs3804099 C/T and rs3804100 C/T. PHASE software was used for haplotype reconstruction. Genetic associations were examined using a chi-square test. Results: We found that the TLR2 rs3804099 TT was significantly more prevalent in EO-BD than in LO-BD patients (corrected p (pc)=0.024). After excluding family history of psychiatric disorders, we also found that the TLR2 rs4696480 TT genotype was significantly more prevalent in EO-BD as compared to LO-BD and controls (pc=0.002 and 0.002). Homozygous state for the insTTT haplotype, carrying the above mentioned risk genotypes, was significantly more frequent in EO-BD than in LO-BD patients (pc=0.007) and in EO-BD without family history of psychiatric disorders as compared to (i) those with positive history (pc=0.03), (ii) with LO-BD without family history (pc=0.001) and (iii) with HC (pc=0.009). Limitations: Confirmation by replication in independent BD cohorts is warranted. Conclusions: Our data suggest the potential role of TLR2 genetic variants in the pathogen-mediated susceptibility to BD. [Copyright &y& Elsevier]

Highlights: [•] CCl4-induced elevation of serum ALP and TBIL was reduced in TLR2−/− mice. [•] CCl4-induced liver collagen deposition was attenuated in TLR2−/− mice. [•] CCl4-induced inflammatory response was ameliorated in TLR2−/− mice. [•] CCl4-induced activation of MAPK and NF-κB signaling pathways was attenuated in TLR2−/− mice. [Copyright &y& Elsevier]

Propionibacterium acnes ( P. acnes) is a well-known acne-inducing factor which causes inflammatory skin lesions by enhancing cytokine production through toll-like receptor 2 (TLR2). Green tea extract catechin has been documented to possess anti-inflammatory effects. However, little is known about the mechanisms involved or any direct effect of green tea catechin on acne. The present study investigated the therapeutic effects and mechanism of polyphenon-60, also known as green tea catechin compound, on acne in vitro and in vivo. In a clinical study using topical polyphenon-60 treatment, acne patients showed symptomatic improvement with decrease in the number of comedos and pustules. To investigate the mechanism underlying the activity of polyphenon-60 in acne therapy, an in vitro study was performed. We found that polyphenon-60 reduced the levels of P. acnes-enhanced TLR2 and interleukin-8 (IL-8) in THP-1 cells, human monocyte cell line and human primary monocytes. Taken together, these data demonstrate that polyphenon-60 has a therapeutic effect on acne by suppressing inflammation, specifically by inhibiting TLR2 expression and IL-8 secretion via down-regulation of extracellular signal-regulated kinases 1/2 (ERK1/2) pathway and activator protein-1 (AP-1) pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression of Toll like receptor 2(TLR2) and interleukin-lß (IL-lß) of cultured human periodontal ligament cells (HPDLCs) activated by Enterococcus faecalis (Efaecalis) lipoteichoic acid (LTA). Methods HPDLCs that were obtained from the periodontal tissues of healthy humans were maintained in pro-per condition. Flow cytometry was used to detect the expression of TLR2 on normal HPDLCs and infectious HPDLCs which were incubated with 0.1, 1, lOμg*mL-1 Efaecalis LTA for 24h. IL-lß was detected by enzyme linked immuno-sorbent assay (ELISA) after incubating with LTA of the above concentration for 12, 24 and 48 h or pretreated with TLR2 neutralizing antibody for lh and then co-cultured with 1 μg*mL-1 LTA for 24 h. Results Efaecalis LTA pro-moted the expression of TLR2 in normal HPDLCs. The difference had statistical significance (P<0.05). IL-lß secre-tion could be detected 12 h after stimulation with LTA and increasingly escalate within 48h(P<0.05). TLR2 neutralizing antibody had no evident effect on IL-lß generation stimulating by Efaecalis LTA. Conclusion Efaecalis LTA can increase the expression of TLR2 and IL-lß in normal HPDLCs. [ABSTRACT FROM AUTHOR]

Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice. Male and female littermate Tlr2+/+ and Tlr2−/− mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production. While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2−/− mice were protected from the adverse effects of HFD compared with Tlr2+/+ littermate controls. Female Tlr2−/− mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2−/− mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2−/− mice did not increase IL-1β expression in response to a NEFA mixture, whereas Tlr2+/+ control tissues did. These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Both interleukin 1 beta (IL-1β) and interleukin-6 (IL-6) are pro-inflammatory cytokines that play a major role in inflammatory diseases as well as cancer. In this work we investigated the signaling pathway involving lipopolysaccharide (LPS)-mediated IL-1β and IL-6 production in murine macrophage cell lines and primary macrophages. We show that in response to LPS, the JAK/STAT pathway is activated, leading to tyrosine phosphorylation at residue 705 on STAT3 and at residue 701 on STAT1, respectively. A newly developed STAT3 specific inhibitor (stattic) blocked LPS-mediated STAT3 tyrosine phosphorylation and led to inhibition of LPS-mediated IL-1β and IL-6 production but not TNF-α production. Knockdown of STAT3 expression via small interfering RNA (siRNA) decreased the level of STAT3 expression in Raw 264.7 cells and decreased STAT3 tyrosine phosphorylation in response to LPS treatment. Quantitative real time PCR and Western analysis of cells treated with inhibitor or STAT3 siRNA after LPS treatment showed a significant reduction of IL-1β and IL-6 mRNA and protein compared to cells treated with LPS alone. Moreover stattic abrogated IL-1β formation in response to extracellular bacteria Staphylococcus aureus and Escherichia coli in murine peritoneal macrophages. This inhibition did not affect caspase-1 activation. These results highlight the complex role of STAT3 in cytokine production and the key role of STAT3 tyrosine phosphorylation in IL-1β and IL-6 production in response to inflammation. [Copyright &y& Elsevier]

• Synergistic action of BASk blocked the activation of NLRP3. • BASk improved endothelial functioning by reducing IL-1β and IL-18. • BASk elevated the release of TGF-β during cholesterol supplementation. • BASk showed its anti-inflammatory potential via reducing COX, 15-LOX, NOS and MPO activities. Progression of chronic inflammatory disease, atherosclerosis is a multifactorial process. Cluster of differentiation 36 (CD36) mediated downstream activation of Toll like receptor 2 (TLR2) and NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome signaling pathway actively participates during chronic inflammation. Nowadays, synergistic combinations of bioactive compounds attained priority in the field of drug discovery and development as therapeutic agents. An investigation regarding the anti-inflammatory potential of a novel drug formulation, BASk which is a combination of three bioactive compounds Betulinic acid (B):Apigenin (A):Skimmianine (Sk) remains the focus area of this research study. We also elucidate the molecular mechanism behind the therapeutic potential of BASk through CD36 mediated activation TLR2-NLRP3 signaling pathway. OxLDL induced hPBMCs used to screen out a suitable combination of BASk via MTT, COX, LOX, NOS and MPO assays. Hypercholesterolemia is induced in rabbits by supplementing with 1% cholesterol + 0.5% cholic acid and treated with BASk (2:2:1) (5 mg/Kg) and atorvastatin (10 mg/Kg) for 60 days. CD36, TLR2, NLRP3, NFκB, cytokines, endothelial damage were quantified by reverse transcription, real time PCR, ELISA, flow cytometry and histopathology. hPBMCs pretreated with BASk at 2:2:1 ratio significantly decreased the activities of COX, 15-LOX, NOS and MPO on OxLDL induction than quercetin. Down regulation of CD36, TLR2, MyD88, TRAF6 by BASk further buttressed NLRP3 inflammasome activation mediated by the transcription factor NFκB. This is in correlation with the effect of BASk by balancing pro (IL-1β, IL-18) and anti-inflammatory (TGF-β) mediators in the aortic endothelial cells. BASk exerted its anti-inflammatory potential by reducing pro-inflammatory mediators during cholesterol supplementation via down regulating CD36 mediated TLR2 – NLRP3 inflammasome cascade. This deciphers a synergistic combination named BASk (2:2:1) as a novel drug formulation against chronic inflammatory disease, atherosclerosis. [ABSTRACT FROM AUTHOR]

Purpose: A defective epithelial barrier has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP). Lactobacilli are shown to restore epithelial barrier defects in gastrointestinal disorders, but their effect on the airway epithelial barrier is unknown. In this study, hence, we evaluated whether the nasopharyngeal isolates Lacticaseibacillus casei AMBR2 and Latilactobacillus sakei AMBR8 could restore nasal epithelial barrier integrity in CRSwNP., Methods: Ex vivo trans-epithelial tissue resistance and fluorescein isothiocyanate-dextran 4 kDa (FD4) permeability of nasal mucosal explants were measured. The relative abundance of lactobacilli in the maxillary sinus of CRSwNP patients was analyzed by amplicon sequencing of the V4 region of the 16S rRNA gene. The effect of spray-dried L. casei AMBR2 and L. sakei AMBR8 on epithelial integrity was investigated in vitro in primary nasal epithelial cells (pNECs) from healthy controls and patients with CRSwNP as well as in vivo in a murine model of interleukin (IL)-4 induced barrier dysfunction. The activation of Toll-like receptor 2 (TLR2) was explored in vitro by using polyclonal antibodies., Results: Patients with CRSwNP had a defective epithelial barrier which positively correlated with the relative abundance of lactobacilli-specific amplicons in the maxillary sinus. L. casei AMBR2, but not L. sakei AMBR8, increased the trans-epithelial electrical resistance (TEER) of pNECs from CRSwNP patients in a time-dependent manner. Treatment of epithelial cells with L. casei AMBR2 promoted the tight junction proteins occludin and zonula occludens-1 reorganization. Furthermore, L. casei AMBR2 prevented IL-4-induced nasal permeability in vivo and in vitro . Finally, the beneficial effect of L. casei AMBR2 on nasal epithelial cells in vitro was TLR2-dependent as blocking TLR2 receptors prevented the increase in TEER., Conclusions: A defective epithelial barrier in CRSwNP may be associated with a decrease in relative abundance of lactobacilli-specific amplicons. L. casei AMBR2 would restore nasal epithelial integrity and can be a novel therapeutic strategy for CRSwNP., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2021 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Calpain 1 is a proinflammatory calcium-activated cysteine protease, which can be partly externalized. Extracellular calpains limit inflammatory processes and promote tissue repair, through cell proliferation and migration. Toll like receptor (TLR) 2 has been identified as a target of extracellular calpains in lymphocytes. The aim was to investigate the externalization of calpain 1 and the release of soluble TLR2 during tumor progression of pulmonary lepidic predominant adenocarcinoma (LPA). Extracellular calpain 1, soluble fragment of TLR2 and cytokines were analyzed by ELISA in bronchoalveolar lavage fluid (BALF) supernatants from patients with LPA (n=68). Source of calpain was analyzed by immunohistochemistry and soluble TLR2 by flow cytometry on polymorphonuclear neutrophils (PMN) and human lung cancer cell lines. Extracellular calpain 1, secreted by tumor cells, was associated to tumor progression, neutrophilic inflammation, with a poor prognostic factor on survival (P=0.003). TLR2 was expressed on PMN and tumor cells and decreased after calpain exposure. Soluble fragment of TLR2 in BALF supernatants was correlated to the extracellular calpain 1 concentration (r=0.624; P<0.001), and its high level was associated with tumor progression and a pro-inflammatory environment. Extracellular calpain 1 secreted by tumor cells, could participate in inflammatory microenvironment and tumor progression through TLR2 in LPA., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Inflammation contributes to the atrial fibrillation (AF) pathogenesis. Among immune cells, monocytes have been suggested to be involved. Few studies have investigated the monocyte Toll- like receptor (TLR)- mediated inflammation in AF patients. Purpose: In this study, we aim to assess monocyte TLR expression in patients with atrial fibrillation. Methods: 30 patients with non- valvular AF and 31 healthy patients in sinus rhythm referred for routine check- up were included. Monocyte TLR-2 and 4 expression were evaluated by flow cytometric analysis in peripheral venous blood samples. Results: 61 subjects (55.7% male, 50.2±11.1 years) were included in the study. Monocyte TLR-2 expression was higher in patients with AF when compared to those in sinus rhythm [18 (10-56) vs. 7 (2-15)%, p<0.001]. Patients with AF also had higher expression of TLR-4 when compared to those with sinus rhythm [19 (9-59) vs. 8 (2-12)%, p<0.001] (Figure). Conclusion: Our study shows that TLR-2 and 4 expression on monocytes is increased in atrial fibrillation. Elucidating underlying exact pathophysiological mechanisms merit further studies. [ABSTRACT FROM AUTHOR]

To investigate the role of toll like receptors (TLRs) 2 and 4 in rhabdomyolysis (RM)-related acute kidney injury (AKI). Wild-type (WT) mice and TLR2 knockout (TLR2 -/- ) or TLR4 knockout (TLR4 -/- ) mice were injected with either saline (sham) or glycerin (to induce RM-related AKI). Samples were collected for detection of 0 h 24 h (Cr) creatinine, urea nitrogen (BUN), creatine kinase (CK), and PAS staining of renal tissues. Serum Cr and BUN level was significantly increased in TLR2 -/- and TLR4 -/- AKI groups more than those in the control group and the WT mice in AKI group. TLR4 -/- AKI group Cr, BUN level, and the pathological damage was lightest. The expression levels of signal transduction proteins in TLR2 -/- and TLR4 -/- AKI group were higher than in the control group, but was lower than that in the wild AKI group, with the TLR4 -/- AKI group having the lowest levels. The expression level of inflammatory factor mRNA in TLR2 -/- and TLR4 -/- AKI groups was higher than that in control group, but was lower than that in wild AKI group, with TLR4 -/- AKI group displaying lowest levels. Knockout of TLRs 2 and 4 decreased kidney inflammation and improved RM-related AKI., Competing Interests: None., (IJCEP Copyright © 2018.)

We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4 + T cells and up-regulate T-cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T-cell expressed TLR2 on CD4 + T-cell differentiation and function, we conducted a gene expression analysis of murine naïve CD4 + T-cells stimulated in the presence or absence of TLR2 co-stimulation. Unexpectedly, naïve CD4 + T-cells co-stimulated via TLR2 showed a significant up-regulation of Il9 mRNA compared to cells co-stimulated via CD28. Under TH9 differentiation, we observed up-regulation of TH9 differentiation, evidenced by increases in both percent of IL-9 secreting cells and IL-9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non-polarizing conditions, TLR2 engagement on CD4 + T-cells had minimal effect on IL-9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN-γ secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4 + T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T-cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: To investigate the role of miR-125b in regulating monocyte immune responses induced by hepatitis C virus (HCV) core protein., Methods: Monocytic THP-1 cells were treated with various concentrations of recombinant HCV core protein, and cytokines and miR-125b expression in these cells were analyzed. The requirement of Toll-like receptor 2 (TLR2) or MyD88 gene for HCV core protein-induced immune responses was determined by the transfection of THP-1 cells with gene knockdown vectors expressing either TLR2 siRNA or MyD88 siRNA. The effect of miR-125b overexpression on TLR2/MyD88 signaling was examined by transfecting THP-1 cells with miR-125b mimic RNA oligos., Results: In response to HCV core protein stimulation, cytokine production was up-regulated and miR-125b expression was down-regulated in THP-1 cells. The modulatory effect of HCV core protein on cellular events was dose-dependent and required functional TLR2 or MyD88 gene. Forced miR-125b expression abolished the HCV core protein-induced enhancement of tumor necrosis factor-α, interleukin (IL)-6, and IL-10 expression by 66%, 54%, and 66%, respectively (P < 0.001), by inhibiting MyD88-mediated signaling, including phosphorylation of NF-κBp65, ERK, and P38., Conclusion: The inverse correlation between miR-125b and cytokine expression after HCV core challenge suggests that miR-125b may negatively regulate HCV-induced immune responses by targeting TLR2/MyD88 signaling in monocytes.

Components of high molecular-weight (PI) obtained from Ascaris suum extract down-regulate the Th1/Th2-related immune responses induced by ovalbumin (OVA)-immunization in mice. Furthermore, the PI down-modulates the ability of dendritic cells (DCs) to activate T lymphocytes by an IL-10-mediated mechanism. Here, we evaluated the role of toll like receptors 2 and 4 (TLR2 and 4) in the modulatory effect of PI on OVA-specific immune response and the PI interference on DC full activation. An inhibition of OVA-specific cellular and humoral responses were observed in wild type (WT) or in deficient in TLR2 (TLR2(-/-)) or 4 (TLR4(-/-)) mice immunized with OVA plus PI when compared with OVA-immunized mice. Low expression of class II MHC, CD40, CD80 and CD86 molecules was observed in lymph node (LN) cells from WT, TLR2(-/-) or TLR4(-/-) mice immunized with OVA plus PI compared with OVA-primed cells. We also verified that PI was able to modulate the activation of DCs derived from bone marrow of WT, TLR2(-/-) or TLR4(-/-) mice induced in vitro by agonists of TLRs, as observed by a decreased expression of class II MHC and costimulatory molecules and by low secretion of pro-inflammatory cytokines. Its effect was accompanied by IL-10 synthesis. In this sense, the modulatory effect of PI on specific-immune response and DC activation is independent of TLR2 or TLR4., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Inflammation and fibrosis are essential elements of diabetic nephropathy (DN). We tested the hypothesis that these elements are dependent upon Toll-like receptor 2 (TLR2) signalling by examining WT and TLR2(-/-) mice in an experimental model of DN. Diabetes was induced in WT and TLR2(-/-) mice by i.p. injection of streptozotocin. Kidney injury was assessed at 6, 12 and 24 weeks after induction of diabetes. Gene expression of TLR2, its endogenous ligands and downstream cytokines, chemokines and fibrogenic molecules were upregulated in kidneys from WT mice with streptozotocin diabetes. TLR2(-/-) mice were protected against the development of DN, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic WT controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR2 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR2 activation in podocytes and tubular epithelial cells (TECs) in vitro, resulting in NF-κB activation, inflammation and TGF-β production. We conclude that TLR2 was required for the full development of inflammation, kidney damage and fibrosis in this model of DN. As TLR2 is known to be expressed by intrinsic kidney cells and as high concentration glucose stimulated podocytes and TECs in vitro to express TLR2 and TLR2 ligands, pro-inflammatory and pro-fibrotic cytokines in a TLR2 dependent manner in the present study, it appears likely that TLR2 signalling in intrinsic kidney cells contributes to the pathogenesis of diabetic nephropathy.

IL-23 is produced by antigen presenting cells and plays critical roles in immune response in rheumatoid arthritis. In this study, we investigated whether the RhoA/Rho-kinase pathway is required to elevate TLR2-mediated IL-23 production in synovial macrophages from patients with rheumatoid arthritis (RA), and then examined the suppressive effect of cilostazol on these pathways. IL-23 production was elevated by lipoteichoic acid (LTA), a TLR2 ligand, and this elevation was more prominent in RA macrophages than in those from peripheral blood of normal control. LTA increased the activation of RhoA in association with increased the nuclear translocation of NF-κB and its DNA-binding activity. Pretreatment of RA macrophages with the pharmacological inhibitors exoenzyme C3 (RhoA), Y27632 (Rho-kinase) or BAY11-7082 (NF-κB) inhibited IL-23 production by LTA. Inhibition of the RhoA/Rho-kinase pathway by these drugs attenuated NF-κB activation. Cilostazol suppressed the TLR2-mediated activation of RhoA, decreased NF-κB activity with down-regulated IL-23 production, and these effects were reversed by Rp-cAMPS, as an inhibitor of cAMP-dependent protein kinase. The expression of IL-23, which colocalized with CD68⁺ cells in knee joint of CIA mice, was significantly attenuated by cilostazol along with the decreased severity of arthritis. Taken together, the RhoA/Rho-kinase pathway signals TLR2-stimulated IL-23 production in synovial fluid macrophages via activation of NF-κB. Thus it is summarized that cilostazol suppresses TLR2-mediated IL-23 production by suppressing RhoA pathway via cAMP-dependent protein kinase activation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Stress can enhance or suppress immune functions depending on a variety of factors. Our previous studies observed that Toll-like receptor 2 (TLR2) participates in chronic restraint stress-induced immune dysfunction. However, the mechanism by which TLR2 prevents immune suppression remains elusive. Our investigation found that stimulation of TLR2 by peptidoglycan (PGN) significantly attenuates splenocyte apoptosis and markedly blocks alterations of anti-apoptotic and apoptotic proteins. Activation of TLR2 inhibits chronic stress-reduced phosphorylation of c-Jun N-terminal kinase (JNK) and diminishes chronic stress-induced up-regulation of corticosterone production. Additionally, our data show that chronic stress causes a dramatic decrease of cytokine IL-2 level but an increase of IL-4 and IL-17 in CD4(+) T cells. Interestingly, PGN could block these alterations of cytokine levels. Collectively, our studies demonstrate that stimulation of TLR2 attenuates chronic stress-induced immune suppression by modulating apoptosis-related proteins and immunoregulatory agents., (Copyright © 2013 Elsevier Inc. All rights reserved.)