fr-167653 and Body-Weight

To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.. BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4(+) T cell and F4/80(+) macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR.. The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were found to be markedly reduced in FR167653-treated DSS mice.. Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1beta and TNF-alpha expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.

Topics: Animals; Antigens, Differentiation; Body Weight; CD4-Positive T-Lymphocytes; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Interleukin-1beta; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred BALB C; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyrazoles; Pyridines; RNA, Messenger; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha

Effects and mechanisms of FR167653, 1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4] triazin-2-yl]-2-phenylethanedione sulfate monohydrate, a dual inhibitor of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on rat adjuvant arthritis (AA) was investigated. Complete Freund's adjuvant was used to induce AA in rats. Secondary paw swelling of AA rats was measured, and polyarthritis index was scored. Synoviocytes were separated by the method of collagenase and DNase digestion. Synoviocytes proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. TNF-alpha, IL-1 and interleukin-10 (IL-10) production of synoviocytes was measured with ELISA. The expression of IL-10 mRNA of synoviocytes was determined using RT-PCR. There were significant secondary inflammatory reactions in AA rats, which accompanied with the decrease of body and immune organs weight simultaneously. The administration of FR167653 (4, 12, 36 mg/kg, subcutaneously (s.c.)) inhibited the inflammatory response and restored the weight of body and immune organs of AA rats. Synoviocytes proliferation of AA rats significantly increased, and the levels of TNF-alpha and IL-1 in supernatants of synoviocytes in AA rats were also elevated compared with the sham group. The administration of FR167653 (4, 12, 36 mg/kg, s.c.) reduced the above changes significantly. In contrast to TNF-alpha and IL-1, IL-10 production and the level of its mRNA of synoviocytes in AA rats were apparently decreased. FR167653 (4, 12, 36 mg/kg, s.c.) markedly increased IL-10 in synoviocytes at protein and transcription level. The results indicated that FR167653 had a beneficial effect on rats AA due to modulating inflammatory cytokines production of synoviocytes, which played a crucial role in pathogenesis of this disease.

Topics: Animals; Arthritis, Experimental; Body Weight; Cell Proliferation; China; Disease Models, Animal; Down-Regulation; Freund's Adjuvant; Injections, Subcutaneous; Interleukin-1; Interleukin-10; Isoxazoles; Knee Joint; Leflunomide; Male; Organ Size; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Spleen; Synovial Fluid; Thymus Gland; Tumor Necrosis Factor-alpha