Lubricin as a Therapeutic and Potential Biomarker in Sepsis.

Proteoglycan 4 (or lubricin), a mucin-like glycoprotein, was originally classified as a lubricating substance within diarthrodial joints. More recently, lubricin has been found in other tissues and has been implicated in 2 inflammatory pathways within the cell, via the Toll-like receptors (TLRs) and CD44. Lubricin is an antagonist of TLR2 and TLR4, and appears to enter cells via the CD44 receptor. Because of lubricin's action on these receptors, downstream processes of inflammation are halted, thereby preventing release of cytokines (a hallmark of inflammation and sepsis) from the cell, indicating lubricin's role as a biomarker and possible therapeutic for sepsis.

Association of Breastfeeding Duration with Susceptibility to Allergy, Influenza, and Methylation Status of TLR1 Gene.

Background and Objectives: This study aimed to investigate the possible association between exclusive breastfeeding duration during early infancy and susceptibility to allergy and influenza in adulthood. Furthermore, we also investigated the association of breastfeeding duration with DNA methylation at two sites in the promoter of the toll-like receptor-1 (TLR1) gene, as well as the association between DNA methylation of the toll-like receptor-1 (TLR1) gene and susceptibility to different diseases. Materials and Methods: Blood samples were collected from 100 adults and classified into two groups according to breastfeeding duration (<6 months and ≥6 months) during infancy. Subjects were asked to complete a questionnaire on their susceptibilities to different diseases and sign a consent form separately. Fifty-three samples underwent DNA extraction, and the DNA samples were divided into two aliquots, one of which was treated with bisulfite reagent. The promoter region of the TLR1 gene was then amplified by polymerase chain reaction (PCR) and sequenced. Results: We found a significant association between increased breastfeeding duration and a reduction in susceptibility to influenza and allergy, as well asa significant reduction in DNA methylation within the promoter of the TLR1 gene. No association was found between DNA methylation and susceptibility to different diseases. Conclusions: The findings demonstrate the significance of increased breastfeeding duration for improved health outcomes at the gene level.

Evaluation of Toll-like receptor expression profile in patients with psoriasis vulgaris.

TLRs are thought to play a role in the pathophysiology of such dermatological diseases as leprosy, acne and psoriasis. The study included 20 patients with plaque psoriasis, as well as 20 healthy age- and gender-matched control subjects. Real-time polymerase chain reaction evaluation was made of the messenger RNA expression of TLRs 1-10 in lesional tissue and peripheral blood mononuclear cell samples in psoriasis patients. TLR 3, 5, 6, 7, 9 and 10 lesional tissue mRNA expressions were increased significantly when compared to the expression levels in the PBMCs of the same patients (p = 0.0082, p = 0.0176, p = 0.0239, p = 0.0261, p = 0.0223, p = 0.0206). A comparison of the TLR expression in the PBMCs of healthy subjects and the PBMCs of patients with psoriasis showed a significant increase in the TLR 1, 8 and 10 mRNA expressions in the patient group (p < 0.0001, p < 0.0001, p = 0.0035). The TLR 5 mRNA expression was significantly higher in the control group than in the patient group (p = 0.0037). To the best of our knowledge, this is the first study in literature to evaluate mRNA TLR expression levels in the lesional tissue and PBMCs of patients with psoriasis.

Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome.

Context: Inflammation and insulin resistance (IR) are often present in polycystic ovary syndrome (PCOS). Objective: We determined the effect of saturated fat ingestion on circulating lipopolysaccharide (LPS) and mononuclear cell (MNC) toll-like receptor-4 (TLR-4) and suppressor of cytokine signaling-3 (SOCS-3) in women with PCOS. Design: Cross-sectional study. Setting: Academic medical center. Patients: Nineteen reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory control subjects (10 lean, 9 obese). Main Outcome Measures: LPS and TNFα levels were measured in plasma. TLR-4 and SOCS-3 mRNA and protein content were quantified in MNC from blood collected after fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood collected after fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results: Regardless of PCOS status, subjects who were obese had lipid-induced increases in circulating LPS and TLR-4 protein content compared with subjects who were lean. Lean and obese women with PCOS had lipid-induced increases in plasma TNFα and SOCS-3 mRNA and protein content compared with lean control subjects. Both PCOS groups had lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The LPS and SOCS-3 responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion: In PCOS, lipid-induced LPS-mediated inflammation through TLR-4 is associated with obesity and worsened by PCOS, whereas lipid-induced increases in SOCS-3 may represent an obesity-independent, TNFα-mediated mechanism of IR.

Genomic organization and transcript profiling of the bovine toll-like receptor gene cluster TLR6-TLR1-TLR10.

Toll-like receptors (TLRs) are a family of recognition receptors playing a crucial role in the innate immune system. Different combinations of TLRs are thought to be crucial for effective immune response, thus insight into the organization and expression of TLRs is important for understanding disease resistance. Mastitis is the most frequent and costly disease in dairy production, and the innate immune system is considered to be important in the first line defence against this disease. In the present paper we have characterized the genomic organization of TLR6-TLR1-TLR10 in a approximately 50 kb region of bovine chromosome 6, including 5'-untranslated exons not previously described. A method for gene expression analysis was developed and used for transcription profiling of the three paralogous genes in different bovine tissues. The expression analysis showed similar expression profiles for TLR1 and TLR6, which indicate a co-regulation of these two genes in cattle. TLR10 had a different expression profile, pointing toward a stronger functional diversification compared to TLR1 and TLR6. The differences in expression are in accordance with the evolutionary history of this gene cluster, where TLR10 diverged from the common ancestral gene before the duplication event that created TLR1 and TLR6.