Association of the Smad3 and NFATc2 gene polymorphisms and their serum levels with susceptibility to rheumatoid arthritis in Polish cohorts.

One among many factors involved in induction of rheumatoid arthritis (RA) are T cells, the differentiation of which depends upon a unique combination of stimulants and subsequent activation of diverse transcription factors. The aim of this study was to identify polymorphic variants in Smad3 and NFATc2 genes and their possible association with susceptibility to and severity of RA. A total of 272 RA patients, 321 for Smad3 and 304 for nuclear factor of activated T cells (NFAT)c2 healthy individuals, were examined for rs6494629 C/T and rs2289263 T/G Smad3 and rs880324 NFATc2 gene polymorphisms using the polymerase chain reaction-fragment length polymorphism (PCR-RFLP) method and TaqMan single nucleotide polymorphism (SNP) genotyping assay, respectively. Serum Smad3 and NFATc2 levels in RA patients and controls were measured by enzyme-linked immunosorbent assay (ELISA). The rs6494629 C/T Smad3 gene polymorphism under the recessive (TT versus CC+CT) and over-dominant (CC+TT versus CT) models were associated with RA (P=0.014 and P=0.008, respectively). Smad3 rs2289263 T/G revealed differences in the case-control distribution in co-dominant, recessive and over-dominant models (P=0.037, P=0.010, P=0.034). Overall, rs6494629 C/T and rs2289263 T/G Smad3 gene polymorphisms were in a weak linkage disequilibrium (LD) with D'=0.116 and r(2)=0.004. After Bonferroni correction, the genotype-phenotype analysis showed no significant correlation of the Smad3 rs6494629 C/T and rs2289263 T/G and NFATc2 rs2289263 TT polymorphisms with disease activity, joint damage and extra-articular manifestation in RA patients. Serum Smad3 and NFATc2 levels were significantly higher in RA patients than in control groups (both P=0 0000). The present findings indicated that Smad3 genetic polymorphisms may be associated with the susceptibility to RA in the Polish population.

Current overview of functions of FoxO proteins, with special regards to cellular homeostasis, cell response to stress, as well as inflammation and aging.

FoxO transcription factors act at the interconnections between metabolic pathways inducible by many important signal transducers and mediators, such as p53, Ikk-ß, NFKB, Akt, sirtuins, PTEN, and others. This may account for a crucial significance of disruptions in FoxO functions both in many kinds of diseases (including cancer, chronic inflammatory diseases, degenerative diseases, obesity, polymetabolic syndrome) and in some disease-like conditions (such as inflammaging, cachexia related to chronic inflammation, cancer-promotion by some chronic inflammatory responses, and the aging process itself). This paper reviews complex interactions between FoxOs and other signal transducers, trying to pinpoint how exactly disruptions of FoxO functions may occur, and how they may contribute to occurrence, development or complications of the conditions mentioned above.

Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA).

Interleukin-17F (IL-17F) is a novel proinflammatory cytokine. IL-17F gene is an excellent candidate for chronic inflammatory disease. We investigated the association between rheumatoid arthritis (RA) and His161Arg (7488A/G; rs763780) and Glu126Gly (7383A/G; rs2397084) polymorphism of IL-17F gene. The gene polymorphisms in 220 Polish patients with RA and 106 healthy subjects were amplified by polymerase chain reaction with restriction endonuclease mapping. Overall, the polymorphisms of the IL-17F gene were not correlated with susceptibility to RA in Polish population. However, the IL-17F His161Arg variant was associated with parameters of disease activity, such as number of tender joints, HAQ score or DAS-28-CRP. Moreover, our findings have shown that Glu126Gly IL-17F gene polymorphism may be correlated with longer disease duration in patients with RA. Our results for the first time showed the relationship between IL-17F gene polymorphisms and severity of RA.

IL-23 in the pathogenesis of rheumatoid arthritis.

Interleukin-23 (IL-23) is a heterodimeric cytokine belonging to the IL-6/IL-12 family that plays a key role in several of autoimmune and inflammatory disorders. This family contains the 34 type I cytokine receptor chains and 27 ligands, which share structural and functional similarities, but on the other hand they display distinct roles in shaping Th cells responses. IL-12 family cytokines have not only proinflammatory effects but they also promote inflammatory responses. IL-23 is composed of the p40 subunit in common with IL-12, and with a unique p19 subunit. IL-23 binding to an IL-23 receptor expressed on dendritic cells, macrophages and monocytes triggers the activation of Jak2 and Tyk2, which in turn phosphorylates STAT1, STAT3, STAT4 and STAT5 as well as induce formation of STAT3-STAT4 heterodimers. IL-23 is one of the essential factors required for the survival and/or expansion of Th17 cells, which produce IL-17, IL-17F, IL-6 and TNF-alpha. Th17 cells stimulated by the IL-23 promote osteoclastogenesis through production of IL-17, which induce receptor activator of NF-kappa B ligand on mesenchymal cells. The IL-23-IL-17 axis includes Th17 cells and plays a key role in the development of autoimmune arthritis.

Involvement of histamine and histamine H2 receptors in nicotinamide-induced differentiation of human amniotic epithelial cells into insulin-producing cells.

OBJECTIVE AND DESIGN: Human amniotic epithelial cells (HAEC) resemble stem cells in their ability to differentiate into all three germ layers: endoderm, mesoderm, and ectoderm. Histamine receptors are expressed on HAEC. We examined the influence of histamine, and H(1) and H(2) antagonists on the generation of pancreatic islet beta-like cells from HAEC. MATERIALS AND METHODS: HAEC were isolated after term pregnancies (N = 12) and cultured for 14 days with nicotinamide (10 mM) in normoxia. Altogether, 72 cultures were established. Histamine (100 microM) effects were investigated with mepyramine (10 microM) or cimetidine (10 microM). After 7 and 14 days, the mean concentration of C-peptide (MCCP) in the culture medium was measured immunoenzymatically as a marker of pancreatic differentiation. RESULTS: MCCP was approximately threefold higher on day 14, compared to day 7. Histamine significantly increased MCCP, and more evident differences were observed after 7 days of culture than after 14 days. The mean percent increase +/-SEM in MCCP amounted to 142.19 +/- 21.7 and 79.03 +/- 12.35 compared to the controls on day 7 and 14, respectively. H(2) blockade significantly reduced histamine-related increase in MCCP, both on day 7 and 14 by 88.7 +/- 14.3 and 39.2 +/- 12.4%, respectively. H(1) receptor antagonist did not affect MCPP. CONCLUSION: Nicotinamide-induced pancreatic differentiation of HAEC into beta-like cells may be augmented, probably at its earlier stage, by histamine acting via H(2) receptors.

Cryotherapy decreases histamine levels in the blood of patients with rheumatoid arthritis.

INTRODUCTION: Conventional physiotherapy (electrotherapy, magnetic fields), kinesitherapy, and whole-body cryotherapy (plus kinesitherapy) are used to relieve pain and inflammation or to improve function in rheumatic diseases. The aim of this study was to investigate the effects of different physiotherapies and cryotherapy on biochemical blood parameters of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). MATERIALS AND METHODS: Twenty patients with RA and 17 patients with OA received whole-body cryotherapy at -140 to -160 degrees C for 2 to 3 min, once daily for 4 weeks. The second group of patients (24 with RA and 28 with OA) received conventional physiotherapy for 4 weeks. We measured the parameters of neutrophil activation (respiratory burst, calprotectin) and markers of cartilage metabolism [N-acetyl-beta-D-hexosaminidase (NAHase), ectonucleotide pyrophosphohydrolase (NTPPHase)] twice: before and 3 months after cryotherapy or physiotherapy. RESULTS: We showed, for the first time, that cryotherapy significantly reduced (P < 0.001) histamine levels in the blood of patients with RA. The effect was long-lasting (for at least 3 months). The levels of blood histamine in patients with OA were not changed significantly. Cryotherapy also downregulated the respiratory burst of PMNs and NAHase activity and upregulated calprotectin levels and the activity of NTPPHase. However, these changes were not statistically significant. In contrast, there were no significant changes in histamine levels or the other biochemical parameters measured in groups of patients treated only with physiotherapy and kinesitherapy. CONCLUSION: It may be concluded that the beneficial clinical effects of cryotherapy in RA patients are in part due to the action on the production, release, or degradation of histamine.

Histamine in pericarditis of children with congenital heart malformations.

INTRODUCTION: Congenital heart malformations are risk factors that make children susceptible to infections resulting in inflammation. MATERIAL AND METHODS: The concentration of histamine as a modulator of inflammation was quantified in pericardial fluid and expression of histamine H(4) receptor (H(4)R) and histamine-releasing factor (HRF) was determined at mRNA and protein levels. Samples of pericardium and pericardial fluid were obtained during cardiac reconstruction surgery in children. RESULTS: In children with pericarditis, increased levels of histamine were found and expression of H(4)R was localized on mast cells. Expression of HRF was independent of presence or absence of inflammation in pericardium and was localized within stationary epithelial cells. CONCLUSION: Results indicate that involvement of H4R in pericardial inflammation depends on penetration of mast cells into inflamed tissue, but HRF may not be directly involved in inflammatory reaction of the pericardium.

Antihistaminic drugs modify casein-induced inflammation in the rat.

INTRODUCTION: All known antihistaminics may affect several inflammatory events, including chemotaxis, the survival of eosinophils, and the release of chemokines and cytokines from different sources, thus highlighting the potential for modulating chronic inflammation and immune responses. The aim of the study was to examine the effect of H(1)-H(4) antihistaminic drugs in an acute model of casein-induced inflammation in rat. MATERIALS AND METHODS: Inflammation was induced by injection of a 12% solution of casein into the peritoneal cavity of male Wistar rats. The rats were treated intraperitoneally with pyrilamine maleate (10 mg/kg), cimetidine (25 mg/kg), thioperamide maleate (2 mg/kg) or ciproxifan hydrogen maleate (0.14 mg/kg) twice: 2 hours prior and 4 hours after casein administration. The level of histamine in blood and chemiluminescence of stimulated and unstimulated PMNs was measured. RESULTS: The level of histamine in the casein-induced inflammation group was higher than in the control group. Treatment with pyrilamine and ciproxifan additionally increased the level of blood histamine during the inflammatory response. Peripheral blood neutrophils from rats with casein-induced inflammation tended to respond less to zymosan stimulation than the neutrophils in the controls. Selective H(1) and H(3) antagonists injected into the rats with casein-induced inflammation significantly increased the response of the neutrophils to zymosan (p < 0.01). CONCLUSION: Histamine produced or released into the blood in the course of experimental inflammation exerts its effects on the PMN-s via stimulation of H(1) and H(3) receptors.

Systemic lupus erythematosus and the extended major histocompatibility complex--evidence for several predisposing loci.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease reported to be associated with several alleles in the HLA complex. The purpose of this study was to systematically examine the extended HLA complex (xMHC) in order to get an overview of the primary predisposing genetic factors. MATERIALS AND METHODS: One hundred and sixty-four SLE patients and 254 healthy, unrelated controls were genotyped for HLA-DRB1, -B and -A alleles, as well as 13 microsatellites markers covering the xMHC. Moreover, we selected 335 additional controls matched with the patients for the HLA haplotypes showing the strongest associations, in order to look for additional predisposing loci. RESULTS: Two regions of the xMHC showed associations: the region covering DRB1 to B, and the extended class I region. Explicitly, DRB1*03 and B*08 displayed strong associations with SLE, which seem to be independent of each other. Furthermore, associations were seen with alleles at microsatellites D6S2225 and D6S2223, located about 3.6 Mb telomeric of HLA-B, and these were not secondary to the associations found with DRB1*03 and B*08. CONCLUSION: Both the DRB1*03 and the B*08 alleles display disease association, either implicating involvement of both alleles or caused by another yet unidentified gene(s) in linkage disequilibrium. The associations found in the extended class I region could be markers for a 'novel' predisposing locus (loci) in SLE, adding to the risk conferred by DRB1*03 and B*08. Interestingly, this region has been shown to also be associated with other autoimmune diseases, hence the gene(s) might confer a general propensity for autoimmunity.