Candesartan inhibits inflammation through an angiotensin II type 1 receptor independent way in human embryonic kidney epithelial cells.

Besides stimulating vasoconstriction, Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication. We previous have demonstrated that a higher dose of candesartan plays a protective role after kidney injury. However, whether candesartan could exhibit anti-inflammatory effects remains unclear. Here, by stimulating isolated human embryonic kidney epithelial cells with tumor necrosis factor-α (TNF-α), we observed the anti-inflammation capacity of candesartan ex vivo. It was found that pre-treat with candesartan significantly suppressed transforming growth factor-ß (TGF-ß) and interleukin-6 (IL-6) expression after incubation with TNF-α. Surprisingly, silence of angiotensin II type 1 receptor has little effects on reducing TGF-ß or IL-6 products. Furthermore, candesartan inhibited TNF-α-induced oxidative stress in the primary cultured tubular epithelial cells. Overall, our data indicates that candesartan suppresses TNF-α-induced inflammatory cytokine production by inhibiting oxidative stress, rather than block AT1 receptor activity.

Lymphotoxin in physiology of lymphoid tissues - Implication for antiviral defense.

Lymphotoxin (LT) is a member of the tumor necrosis factor (TNF) superfamily of cytokines which serves multiple functions, including the control of lymphoid organ development and maintenance, as well as regulation of inflammation and autoimmunity. Although the role of LT in organogenesis and maintenance of lymphoid organs is well established, the contribution of LT pathway to homeostasis of lymphoid organs during the immune response to pathogens is less understood. In this review, we highlight recent advances on the role of LT pathway in antiviral immune responses. We discuss the role of LT signaling in lymphoid organ integrity, type I IFN production and regulation of protection and immunopathology during viral infections. We further discuss the potential of therapeutic targeting LT pathway for controlling immunopathology and antiviral protection.

Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and ß-catenin activation.

OBJECTIVE: The aetiology of OA is not fully understood although several adipokines such as leptin are known mediators of disease progression. Since leptin levels were increased in synovial fluid compared to serum in OA patients, it was suggested that joint cells themselves could produce leptin. However, exact mechanisms underlying leptin production by chondrocytes are poorly understood. Nevertheless, prednisolone, although displaying powerful anti-inflammatory properties has been recently reported to be potent stimulator of leptin and its receptor in OA synovial fibroblasts. Therefore, we investigated, in vitro, spontaneous and prednisolone-induced leptin production in OA chondrocytes, focusing on transforming growth factor-ß (TGFß) and Wnt/ß-catenin pathways. DESIGN: We used an in vitro dedifferentiation model, comparing human freshly isolated hip OA chondrocytes cultivated in monolayer during 1 day (type II, COL2A1 +; type X, COL10A1 + and type I collagen, COL1A1 -) or 14 days (COL2A1 -; COL10A1 - and COL1A1+). RESULTS: Leptin expression was not detected in day1 OA chondrocytes whereas day14 OA chondrocytes produced leptin, significantly increased with prednisolone. Activin receptor-like kinase 1 (ALK1)/ALK5 ratio was shifted during dedifferentiation, from high ALK5 and phospho (p)-Smad2 expression at day1 to high ALK1, endoglin and p-Smad1/5 expression at day14. Moreover, inactive glycogen synthase kinase 3 (GSK3) and active ß-catenin were only found in dedifferentiated OA chondrocytes. Smad1 and ß-catenin but not endoglin stable lentiviral silencing led to a significant decrease in leptin production by dedifferentiated OA chondrocytes. CONCLUSIONS: Only dedifferentiated OA chondrocytes produced leptin. Prednisolone markedly enhanced leptin production, which involved Smad1 and ß-catenin activation.

Lymphotoxin ß receptor signaling promotes development of autoimmune pancreatitis.

BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. METHODS: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and ß specifically in acinar cells (Ela1-LTab mice). RESULTS: Messenger RNA levels of LTα and ß were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαß (Ela1-LTαß) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαß did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTßR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS: Overexpression of LTαß specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTßR ligands might be used to treat patients with AIP.

Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in rats.

PURPOSE: We aimed to define the morphologic effects of valproate (VPA) and oxcarbazepine (OXC) on ovarian folliculogenesis in rats. METHODS: Forty female wistar rats (21-24 days old and weighted between 46.4 and 55.3 g) were divided equally into 4 experimental groups, which were applied tap water (control group), 300 mg/kg/day VPA, 100 mg/kg/day OXC, and both VPA and OXC via gavage for 90 days. Ovaries of the rats on proestrous and diesterous phase of estrous cycle according to daily vaginal smear were taken out and placed in a fixation solution. Immunohistochemical and apoptosis (TUNEL) staining protocols were applied. RESULTS: The number of follicles decreased and that of corpora lutea increased significantly in OXC, VPA, and OXC+VPA treated groups compared with control group (p < 0.05). The number of TUNEL positive ovarian follicles was 1.40 +/- 0.52 in control group, but it significantly increased to 3.50 +/- 0.53, 3.50 +/- 0.53, and 4.90 +/- 0.88 in VPA, OXC, and VPA+OXC groups (p < 0.0001). The increase in the number of TUNEL positive granulosa cells was also significant for OXC and VPA+OXC groups (p < 0.0001). Immunohistochemical HSCORE decreased for TGF beta 1 and IGF1 staining and increased for P53 staining in all drug groups compared with control group (p < 0.001). Intensity of P53 labeling increased, while intensity of TGF beta 1, IGF-1, and GDF-9 immunoreactivity decreased significantly in all drug groups compared with control group (p < 0.001). CONCLUSION: Long-term treatment with VPA or OXC from prepuberty to adulthood causes apoptosis and deterioration of folliculogenesis in rat ovarian follicles.

Relationship between circulating tumor necrosis factor system and bone mass before and after estrogen plus progestogen therapy.

OBJECTIVE: The aim of his study was to investigate the relationship between the circulating tumor necrosis factor (TNF) system and bone mineral density (BMD) before and after estrogen plus progestogen therapy (EPT). METHODS: Serum levels of TNF-alpha, TNF-beta, soluble TNF receptor (sTNFR) 1, sTNFR2, and bone turnover markers and BMDs at the lumbar spine and proximal femur were measured in 192 postmenopausal Korean women. Among all women, 70 were treated with sequential EPT for 1 year. RESULTS: BMDs at all skeletal sites and bone turnover markers were not correlated with serum TNF and sTNFR. After adjustment for age, years since menopause, and body mass index, serum TNF-beta levels were significantly lower in osteoporotic women than in normal women, whereas serum levels of TNF-alpha and sTNFR did not differ among normal, osteopenic, and osteoporotic postmenopausal women. After 6 months of EPT, serum TNF-beta levels increased significantly (P < 0.05), whereas serum TNF-alpha, sTNFR1, and sTNFR2 levels were unchanged. The 1-year changes in BMD at the lumbar spine and proximal femur after EPT were not correlated with the basal levels of serum TNF-alpha and sTNFR and their changes 6 months after EPT. CONCLUSIONS: In the circulating TNF system, only serum TNF-beta levels were lower in osteoporotic postmenopausal women compared with normal postmenopausal women and increased after EPT, but changes in circulating TNF and sTNFR after EPT had no association with changes in bone markers and BMD. The circulating TNF system may not be clinically useful for predicting BMD and bone response after EPT.