To assess roles of cytokines in the inflammatory process, we examined local production of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1, a member of the CXC chemokine in rats), in the exudates of carrageenin induced pleurisy of rats. All four cytokine levels began to increase at 1-2h, and their production preceded the influx of neutrophils, and peaked at 3-5h, whereas the exudate volume and leukocyte number still continued to increase. When recombinant human (rh) TNFα or rhlL-1α was injected into the pleural cavity, the pleural CINC-1 level rapidly increased, preceding the neutrophil infiltration. A sharp rise in IL-6 level in the plasma, followed by an increase in T-kininogen, an acute-phase protein, was also observed. Intrapleural injection of rhIL-8 or CINC-1 caused neutrophil infiltration in a protein synthesis independent manner. Treatment with indomethacin, an anti-inflammatory drug, increased TNF and IL-1 levels but suppressed IL-6 level in the exudate of rats with pleurisy, whereas dexamethasone suppressed all these cytokine levels. Prostaglandins (PGs) and dibutyryl cAMP reduced the production of TNF and IL-1, while they increased that of IL-6 and CINC-1 from rat pleural resident cells. The above results clearly indicate that proinflammatory cytokines, TNF, IL-1, IL-6 and CINC-1 were produced locally. Moreover, these results suggest that these proinflammatory cytokine production could be regulated by inflammatory stimuli and also by other mediators such as PGE₂ and PGI₂ concomitantly produced in the inflammatory sites.

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Rats were fed either linoleate-rich safflower oil or α-linolenate-rich perilla oil diets. The brightness-discrimination learning performance was significantly higher in the perilla oil group than in the safflower oil group. In synapses of hippocampus CA1, the density of synaptic vesicles was significantly higher in the perilla oil-fed rats than the safflower oil-fed rats. The number of terminals with low density of synaptic vesicles was increased in the safflower oil group after the learning. Fourier transform infrared spectroscopy of rat brain microsomes revealed that the second derivative spectrum at 1050-1250 cm^-1showed difference between perilla and safflower oil groups after the learning. The infrared band at 1727 cm^-1 in the safflower oil group moved to the higher wavenumber position at 1731 cm^-1in the perilla oil group after the learning. The results suggested that the hydrogen bond of fatty acid ester (sn-2) with water was weakened and moved inward of the membrane, and resulted in a lowered hydration. This was confirmed by the weakened reactivity of the membrane phospholipids to phospholipase A₂ in the perilla oil group after the learning. These results suggested that n-3 polyunsaturated fatty acid-deficiency may affect the turnover of synaptic vesicles in hippocampus with loss of learning ability.

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The serum concentration of serum amyloid-A protein (SAA) and C-reactive protein (CRP) as the acute phase proteins have been measured in 56 patients with rheumatoid arthritis (RA), 18 with systemic lupus erythematosus (SLE), and 18 with Behcet's disease (BD) . In RA patients, SAA and CRP concentration correlated well (r=0.87), though SAA showed a greater incremental increase than CRP. In SLE and BD patients, SAA was raised in 37% of patients with normal CRP. These findings suggest that SAA is a more sensitive marker of inflammation than is CRP.

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Generalized bone loss is recognized as a major event in RA. Both biochemical parameters of bone metabolism and the bone mineral density were investigated in remission, non-steroid treated patients with RA in order to assess bone turnover and bone loss in remission phase RA.
We studied 31 patients of remission RA with good response to DMARDs and compared with remission SLE and normal young adults. Urinary NTx, pyridinoline (PYR), deoxypyridinoline (DPYR) and TRAP, as parameters of bone resorption and serum bone related alkaline phosphatase (ALP III), osteocalcine and ICP (S) were measured in RA, SLE and healthy subjects. Total bone density (TBD), trabecular density (TD) and cortex density (CD) were also evaluated using XCT960 pQCT.
ALP III, osteocalcine and ICP (S) levels were significantly lower in RA compared with 6 healthy subjects, but there was no significant difference between SLE and healthy subjects.
PYR levels were elevated in stage III and IV of RA but were similar between SLE and healthy subjects. TBD including TD and CD was significantly reduced in RA patients compared with the control group. Decreasing ratio of TBD in RA patients was correlated with advancement of RA. However, TBD value in stage IV RA patients were seemingly increased as compression fracture of lumber spine in osteoporosis.
These results suggest that bone metabolism may be uncouple in remission phase RA. Bone formation appeared to be reduced, whereas resorption is increased.

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In this study, we investigated the effects of NSAIDs such as indomethacin and d-2- [4- (3-methyl -2-thenyl) phenyl] propionic acid (M-5011), PGE₂, cAMP-elevating agents (forskolin, DBcAMP, IBMX) on IL-6 and TNF-α production in PBMC. The effects of NSAIDs on IL -6 production in human monocyte cell line (THP -1 cell) were also studied. NSAIDs downregulated IL-6 production, up-regulated TNF-α production and suppressed PGE₂ production in lipopolysaccharide (LPS) -stimulated PBMC. M-5011 down-regulated IL -6 production both at the protein and mRNA levels. The effects of M-5011 on cytokine production was significantly stronger than that of indomethacin, whereas it was opposite on PGE₂ production. The inhibition of IL-6 production by NSAIDs were also observed in THP-1 cells, although NSAIDs did not affect PGE₂ production from THP-1 cells. PGE₂ and CAMP-elevating agents inhibited TNF-α production without affecting IL-6 production in LPS-stimulated PBMC. PGE₂, forskolin and DBcAMP induced a dose dependent elevation of the intracellular concentration of cAMP level, but IBMX induced a constant elevation of that. These results suggest that elevation of cAMP is not entirely responsible for regulation of cytokine production, and the downregulation of IL-6 production by NSAIDs may be partly independent of inhibition of PGE₂ production.

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Urate oxidase (uricase) from Candida utilis, an essential thiol enzyme, was examined for its sensitivity to myeloperoxidase, an oxidant present in neutrophils. Upon exposure to a system composed of myeloperoxidase, hydrogen peroxide and chloride at neutral or moderately alkaline pH, the uricase exhibited comparable activity to the untreated enzyme; but upon exposure at moderately acidic pH, it exhibited less than 8.0±3.0 (mean ± SE, n= 5) % of the activity of the untreated enzyme. Thus the myeloperoxidase-H₂O₂-chloride system significantly inactivated uricase only at moderately acidic pH. This inactivation was prevented by the presence of N-acetylmethionine, a methionine analogue and a thioether compound, or glutathione, a thiol compound analogous to amino acid, indicating that it was due to the oxidation and damage of the methionine residue and/or the thiol group in uricase by the myeloperoxidase system, accompanying the loss of catalytic activity of the uricase.

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