Human ligamentum flavum-derived cells (HFCs) were obtained from surgical samples for a basic experimental study. Purpose: We sought to evaluate the inflammatory response of human ligamentum flavum cells to investigate hypertrophic changes occurring in the ligamentum flavum. Overview of Literature: Lumbar spinal stenosis (LSS) is a disease commonly observed in the elderly. The number of patients with LSS has increased over time, yet the pathomechanisms of LSS still have not been fully elucidated. One of the clinical features of LSS is hypertrophy of the ligamentum flavum, which results in narrowing of the lumbar spinal canal. Some reports have suggested that ligamentum flavum hypertrophy is associated with inflammation and fibrosis; meanwhile, the p38 mitogen-activated protein (MAP) kinase is involved in the hypertrophy of human ligamentum flavum cells. Methods: HFCs were obtained from patients with LSS who underwent surgery. HFCs were stimulated by tumor necrosis factor-α (TNF-α) and a p38 MAP kinase inhibitor, SB203580. Phosphorylation of the p38 MAP kinase was analyzed by western blotting. The concentration of interleukin-6 (IL-6) in the conditioned medium was measured by enzyme-linked immunoassay and IL-6 messenger RNA expression levels were determined by real-time polymerase chain reaction. Results: TNF-α induced the phosphorylation of p38 MAP kinase in a time-dependent manner, which was suppressed by the p38 MAP kinase inhibitor, SB203580. TNF-α also stimulated IL-6 release in both a time-and dose-dependent manner. On its own, SB203580 did not stimulate IL-6 secretion from HFCs; however, it dramatically suppressed the degree of IL-6 release stimulated by TNF-α from HFCs. Conclusions: This is the first report suggesting that TNF-α stimulates the gene expression and protein secretion of IL-6 via p38 MAP kinase in HFCs. A noted association between tissue hypertrophy and inflammation suggests that the p38 MAP kinase inflammatory pathway may be a therapeutic molecular target for LSS.

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Background: Rheumatoid arthritis (RA) is an autoimmune rheumatic disease. Activated B-and T-lymphocytes, mast cells, macrophages, tissue fibroblasts play a leading role in its pathogenesis. The development of autoimmune inflammation is impossible without the influence of a large number of pro-inflammatory cytokines such as IL 1α and β, TNF α, IL 6, IL 17, IL 22. Currently, other classes of biologically active molecules, such as adiponectin, visfatin, nesfatin, fetuin A, are being actively studied in RA [1,2,3,4]. Pre-B-cell colony enhancing factor 1 (PBEF1) stimulates synthesis of matrix metalloproteinases and chemokines, supporting synovial inflammation caused by leukocyte infiltration. A positive correlation between visfatin and C-reactive protein confirms its role as a mediator of inflammation. It is believed that increased concentrations of PBEF1 can stimulate systemic inflammation. Objectives: The study the relationship between serum PBEF1 level and disease activity in RA patients. Methods: We observed 140 patients with a reliable diagnosis of RA, of whom 96 were women and 44 were men. The control group consisted of 20 women and 10 men aged from 22 to 55 years without complaints of pain in the joints during life. PBEF1 concentration in blood serum were determined by indirect enzyme-linked immunosorbent assay using commercial test systems (RaiBiotech, cat№ EIA-VIS-1) according to the manufacturer's instructions. Results: The level of normal values of PBEF1 in healthy individuals with a BMI of 18.5 to 24.9 kg/m2 was 0.14-3.9 ng/ml, with a BMI of 25 to 29.9 kg/m 2 -0 -5.9 ng/ ml. Elevated serum PBEF1 level was detected in 84.29% of RA patients. The ones with elevated PBEF1 levels of significantly more likely to have a higher degree of activity index DAS28 (χ 2 =48,293; p<0,001,), high level of anti-cyclic citrullinated peptide (anti-CCP) (χ 2 =5,386; p=0,0203), higher levels of C-reactive protein (χ 2 =8,159; p=0,0043), erythrocyte sedimentation rate (p<0,001), extraarticular manifestations of the disease (χ 2 =7,354; p=0,0067). Conclusion: PBEF1 can be regarded as an important link in the pathogenesis of rheumatoid arthritis and for the potential molecule for biological therapeutic agents.

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