leptin and Sjogren-s-Syndrome

Dry mouth is the main manifestation of Sjögren syndrome (SS). Quercetin has been reported to alleviate radiation-induced salivary gland damage, yet the effect of quercetin on SS-caused salivary gland damage remains unclear. This study aimed to investigate the effects of quercetin on SS-induced salivary gland damage and the mechanism underlying its therapeutic potential in SS. Here, NOD/Ltj mice were used to spontaneously mimic SS-induced salivary gland inflammation in vivo and salivary gland epithelial cells (SGECs) were stimulated by interferon-γ (IFN-γ) to mimic cell inflammation in vitro. Results showed that quercetin significantly reduced loss of saliva flow, salivary gland damage, cell apoptosis, and inflammatory response in NOD/Ltj mice. Quercetin treatment also significantly reduced the increased serum leptin (LP) levels in NOD/Ltj mice. Furthermore, quercetin blocked the increases in the expression of obesity receptor (OB-R) and its downstream Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling in the salivary glands. In vitro experiments confirmed that quercetin could protect SGECs from IFN-γ-induced cell apoptosis and inflammation through the LP/OB-R-activated JAK2/STAT3 signaling. Hence, quercetin might protect against SS-induced salivary gland damage by relieving cell apoptosis and inflammation by inhibiting the LP/OB-R signaling, providing a new perspective for treating SS-induced dry mouth.

Topics: Animals; Apoptosis; Inflammation; Interferon-gamma; Leptin; Mice; Mice, Inbred NOD; Obesity; Quercetin; Salivary Glands; Sjogren's Syndrome

Sjögren's syndrome (SjS) is a systemic autoimmune disease resulting in a severe dry mouth and dry eyes. Currently, care for patients with SjS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms are uncertain. Leptin activates B cells to induce the secretion of proinflammatory and anti-inflammatory cytokines and is elevated in several autoimmune diseases. In this study, we found the expression of leptin and its receptor OB-R in mouse models of SjS are elevated both locally and systemically during SjS progression. Recombinant serotype 2 adeno-associated viral (rAAV2) vectors expressing either OB-R shRNA (rAAV2-shOB-R) or none (rAAV2-null) were injected into 4 or 16 week-old BALB/c NOD/LtJ (NOD) mice and resulted in a modest reduction in glandular inflammation in the SjS model. In conclusion, Leptin/OB-R signaling may be pathogenically involved in SjS and may serve as a new marker and a potential therapeutic target.

Topics: Animals; Disease Models, Animal; Female; Humans; Inflammation; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Receptors, Leptin; Signal Transduction; Sjogren's Syndrome; Up-Regulation

Metabolic syndrome (MetS) has been described in autoimmune diseases. However, there are scarce data about MetS and adipocytokine profile in primary Sjögren's syndrome (pSS). Seventy-one female pSS patients (American-European Consensus Group Criteria, 2002) aged 18-65 years and 71 age-, race-matched control women were enrolled in this case-control study. Clinical data were collected by a standardized protocol. Blood levels of glucose, cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides, interleukin-1beta (IL-1beta)/IL-6, B-cell activating factor (BAFF), insulin, and leptin/adiponectin/visfatin/resistin were determined. Patients and controls were comparable regarding body mass index (BMI), smoking, sedentariness, and menopause (p > 0.05). MetS (39.4 vs. 16.9 %, p = 0.005), hypertension (p = 0.004), and dyslipidemia (p = 0.002) were more frequent in patients than controls. IL-1beta, IL-6, BAFF, resistin, and adiponectin levels were higher in patients than controls (p < 0.05). pSS patients with MetS (n = 28) had higher BMI, waist circumference, cholesterol, LDL-C, triglycerides, insulin, leptin and HOMA-IR values, and greater hypertension and diabetes rates than pSS patients without MetS (n = 43) (p < 0.05). Current and/or previous prednisone use (75.0 vs. 62.8 %, p = 0.313), current (3.0 ± 4.5 vs. 1.6 ± 3.2 mg/day, p = 0.299), and cumulative prednisone doses (p = 0.495) were similar in both groups. Otherwise, IL-1beta level was higher in MetS patients than in non-MetS patients (p = 0.012), and this finding was confirmed (p = 0.048) by multivariate analysis with adjustments for age, ethnicity, prednisone use, current and cumulative prednisone doses, and duration of use. We identified high MetS frequency and abnormal adipocytokine profile in pSS. The association of MetS with elevated IL-1beta level suggests that inflammation plays an important role in its pathogenesis.

Topics: Adipokines; Adiponectin; Adolescent; Adult; Aged; Blood Glucose; Case-Control Studies; Cholesterol; Female; Humans; Insulin; Insulin Resistance; Interleukin-1beta; Interleukin-6; Leptin; Metabolic Syndrome; Middle Aged; Nicotinamide Phosphoribosyltransferase; Sjogren's Syndrome; Triglycerides; Young Adult

The role of leptin in primary Sjögren's syndrome (SS) pathogenesis is unknown. The aim of this study was to investigate the expression of leptin and leptin receptor (LEPR) in minor salivary glands in patients with SS.. The expression of leptin and LEPR in minor salivary gland specimens obtained from patients with primary SS (n=50) and control subjects (n=50) were examined using immunohistochemical staining.. Acinar cells, epithelial cells and adipocytes in salivary glands can express leptin and LEPR. It was observed that there was intense staining in the focal lymphocytic infiltration areas in SS patients. The intensity of leptin and LEPR staining under microscopy (400×) were graded semiquantitatively as negative, mild, moderate or strongly positive, and scored as 1, 2 or 3, respectively. The expression levels of leptin and LEPR in patients with primary SS were not higher than in controls. There was no significant difference in degrees of leptin and LEPR staining, staining intensity, and immunoreactive scores between groups. The expression of leptin and LEPR were not correlated with autoantibodies such as RF, ANA, anti-Ro, and/or anti-La positivity.. These findings indicate that leptin and its receptors do not play an important role in primary SS pathophysiology.

Topics: Adult; Aged; Female; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Receptors, Leptin; Salivary Glands; Sjogren's Syndrome; Young Adult