Histamine and Histamine H4 Receptor Promotes Osteoclastogenesis in Rheumatoid Arthritis.

Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP-positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA

Association between lower urinary tract symptoms and cigarette smoking or alcohol drinking

Background: Although there have been several studies about the relationship between alcohol or smoking and lower urinary tracts symptoms (LUTS). This study aimed to investigate the association between alcohol or smoking and severity of LUTS in men, as alcohol intake and cigarette smoking is important modifiable lifestyle factors for LUTS. Methods: A cross-sectional analysis has been performed and a total of 86,707 participants in Korean Community Health Survey were included for final analysis. The adjusted odds ratio (OR) or coefficient with 95% confidence interval (CI) estimates were described to show the association between alcohol consumption or cigarette smoking and LUTS. Results: Among the total subjects, 77,398 (89.3%), 7,532 (8.7%), and 1,777 (2.0%) had mild, moderate, and severe symptoms, respectively, according to International Prostate Symptom Score (IPSS) grade. Those who drank alcohol at least once per month were significantly associated with decreased risk of having the worst IPSS grade (OR: 0.80, 95% CI: 0.68 to 0.93). Those who smoked in the past but currently quitted and those who were daily smokers showed significantly increased risk of having the worst IPSS grade (past smoker, OR: 1.26, 95% CI: 1.14 to 1.39; daily smoker, OR: 1.21, 95% CI: 1.10 to 1.34). For nocturia, daily smoking showed positive effect (OR: 0.79, 95% CI: 0.75 to 0.84) whereas heavy alcohol drinking showed negative effect (OR: 1.22, 95% CI: 1.14 to 1.32) Conclusions: Alcohol showed positive effect on LUTS except nocturia whereas cigarette smoking had negative effect on LUTS except nocturia. Daily smoking showed positive effect on nocturia whereas heavy alcohol drinking showed negative effect on nocturia

Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor κB-dependent pathway in patients with rheumatoid arthritis

Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription–polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-α, IL-1β, IL-18 or transforming growth factor-β did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor κB (NF-κB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-κB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-κB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA