Effects of the steroidal anti-inflammatory drug dexamethasone on the antigeninduced activation of c-Jun N-terminal kinase (JNK) was examined. Antigen stimulation of IgE-sensitized rat basophilic leukemia RBL-2 H3 cells induced activation of JNK within a few minutes with maximum activity attained 40 min later. The increase in JNK activity was accompanied with an increase in phosphorylation of c-Jun in the cells. The antigen-induced JNK activation was inhibited by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002 but not by the protein kinase C inhibitors calphostin C and Ro 31-8425. Pretreatment with dexamethasone (10 and 100 nM) for 18 h prominently inhibited the antigen-induced increase in JNK activity in a concentration-dependent manner, while protein levels of JNK were slightly decreased. At least 6-h preincubation with dexamethasone was necessary to inhibit the antigen-induced JNK activation. The phosphorylation of c-Jun induced by the antigen stimulation was reduced by pretreatment with dexamethasone without reduction of the content of c-Jun protein. The antigen-induced activation of the JNK kinase kinase MEKK-1 was also inhibited by pretreatment with dexamethasone. These findings indicate that dexamethasone inhibits the antigen-induced activation of JNK. In conclusion, the inhibition by dexamethasone of JNK activation resulting in the inhibition of c-Jun phosphorylation might be a new mechanism by which dexamethasone down-regulates AP-1 activity and inhibits cytokine production.

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Vasculitis in a clinical and pathological process characterized by inflammation and necrosis of blood vessel walls. The clinical expression depends on the site, type, and size of involved vessels, and the severity of the associated inflammatory features. There have been changes in the concept and many attempts at the classification of vasculitis along clinical evidences, histopathological findings, immunological advances and developments of molecular biological research, since Kussmaul and Maier reported a case of periarteritis nodosa in 1866. The animal models of vasculitides have also been established. Recently, a new classification of primary systemic vasculitis which was classified according to the size of involved vessels was proposed. Although the aetiology of primary systemic vasculitis in this classification is unknown yet, genetic factors and enviromental factors are important for the development of vasculitis. In the above classification, microscopic polyangiitis which is characterized by microvasculitis and positive antineutrophil cytoplasmic antibody (ANCA) is distinct from polyarteritis nodosa which is characterized by the mediumsized arteritis and negative ANCA. ANCA does not only contribute to the classification of vasculitis like this but also has given impetus to the studies on pathogenetic mechanisms and therapeutic strategies. In this paper, recent advances of the study in primary systemic vasculitis syndrome were reviewed.

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Matrix metalloproteinase (MMP) -9 plays an important role in neutrophil extravasation and migration by its ability to degrade the major components of basement membrane. To evaluate the expression of neutrophil MMP-9 (gelatinase) under inflammatory conditions, we examined the levels of MMP-9 and its mRNA in neutrophils from glycogen-induced peritoneal inflammation of guinea pigs. MMP-9 level in peritoneal neutrophils was essentially the same as that in blood neutrophils, although peritoneal neutrophils were assumed to have extracellularly released MMP-9 from the granules during infiltration into the peritoneal cavity. Interestingly, MMP-9 mRNA was expressed more abundantly in peritoneal neutrophils than in blood neutrophils. Moreover, actinomycin D-or cycloheximide-treatment significantly suppressed the MMP-9 levels in blood and peritoneal neutrophils. In addition, when blood neutrophils from non-injected animals were stimulated with 10^-7 M N-formyl-Met Leu-Phe, 10μg/ml lipopolysaccharide, 10 ng/ml phorbol 12-myristate 13-acetate, 10^-8 MIL-8 or 100 U/ml tumor necrosis factor-α, expression of MMP-9 mRNA was markedly increased. The present observations indicate that MMP-9 gene is transcribed, and MMP-9 protein is synthesized in neutrophils during inflammation. Moreover, the transcription of MMP-9 gene can be upregulated in neutrophils by stimulation with inflammatory mediators, even after neutrophils have been matured.

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Apoptosis is induced by reactive oxygen species (ROS) and nitrogen species (RNS) which are produced under inflammatory conditions. Antioxidative enzymes such as superoxide dismutases and glutathione peroxidases (GPx) are known to prevent apoptosis through scavenging cytotoxic ROS. We found that nitric oxide (NO) specifically inhibits GPx activity, resulting in augmentation of peroxides. This suggests that dysfunction of GPx by binding of NO to the active site, selenocysteine, is at leaset in part responsible for the cellular damage. Since imbalance of a redox state caused by overexpression of aldose reductase also induces apoptosis, a significant role of redox system in controlling apoptosis is implicated. We have cloned and analyzed five members of the peroxiredoxin (Prx) gene family, which detoxify peroxides with thioredoxin and/or glutathione as electron donors. Analysis of the fourth member, Prx IV, indicates that it is a secretable form and exerts its protective role outside of the cells. We also demonstrated the essential role of selenocysteine residue in thioredoxin reductase by site specific mutagenesis as well as by deletion analysis of the selenocysteine insertion sequence element located at the 3' -untranslated region of the gene. Possible roles of these redox systems in protection against apoptotic stimuli are discussed.

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Keratinocytes (KC) produce proinflammatory cytokines and prostaglandin E₂ (PGE₂) leading to the skin inflammation induced by ultraviolet radiation (UVR) . UVR-induced inflammation, sunburn, is mainly induced by UVB, but UVA is known to augment its reaction. In order to find if this augmentative effect of UVA is due to the effect of UVA on KC to induce proinflammatory mediators including cyto-kines and PGE₂, normal human KC were cultured and irradiated by UVB and UVA either separately or concomitantly. Levels of mRNA for each cytokine were deter-mined by the reverse transcriptase-polymerase chain reaction (RT-PCR) method and protein production in cultured supernatants was assayed by enzyme-linked im-munosorbent assay (ELISA) or enzyme immunoassay (EIA) . UVB (300 J/m²) induced the expression of IL-6, IL-8, TNF-α, TGF-β1 and GM-CSF mRNA at 24 h after irradiation, while an increase only in IL-6 and IL-8 mRNA levels was observed at 24 h after UVA irradiation (10 kJ/m²) . IL-1α, IL 6, IL-8 and PGE₂ production was increased augmentatively by UVB and UVA, but significant levels of TNF-α, TGF-β1 and GM-CSF protein in cultured supernatants were detected only after UVB irradiation. These results indicate that UVB and UVA differentially regulate the expression and production of KC-derived cytokines and UVA is able to induce proinflammatory mediators from KC additively to UVB. Our results explain the mechanism by which UVA augments UVB-induced skin inflammation.

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Several investigations have been undertaken with regard to the relationship between viral infection and idiopathic pulmonary fibrosis (IPF) . However the results are conflicting. In this study, relationship between IPF and Epstein-Barr virus (EBV) was investigated by examining the antibody in the sera of 47 pathologically-diagnosed IPF patients and by detecting virus DNA in the tissue of 19 specimens from 10 patients using nested polymerase chain reaction methods. Titers of EBV-VCA IgG were significantly higher in IPF patients than those in normal controls (p<0.01) . EBV-DNA was detected in 9 of 10 IPF patients. In contrast, EBV-DNA existed in only 2 of 10 normal tissues from lung cancer patients and in 1 of 7 pulmonary fibrosis tissues from collagen vascular disease patients (p<0.001) . In conclusion, EBV infection may play an important role in pathogenesis of IPF.

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We measured SOD activity, NOx, and free SH level in wobbler mice. Their NOx levels in both brain and spinal cord were significantly higher than those in healthy littermates. In addition, the SOD activity in both brain and spinal cord was lower with a significant difference. Furthermore, it was found that the free SH level in their brain was also lower. These results suggest that free radical might play some role of the motoneuron degeneration in wobbler mice.

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Post-marketing surveillance was undertaken with non-steroidal anti-inflammatory analgesic Relifen^® tablet (nabumetone) in patients with rheumatoid arthritis, low back pain, cervico-omo-brachial syndrome, scapulohumeral periarthritis and osteoarthritis for 6 years from March, 1990 to March, 1996.
Total 5, 347 cases surveyed were collected from 558 medical institutions of all over the country : 5, 266 cases were assessed for safety ; 5, 192 cases were assessed for efficacy.
In 5, 266 cases assessed for safety, adverse reactions occurred in 2.54% (134/5, 255 eases) . Representative manifestations were gastro-intestinal system disorders such as abdominal pain and nausea in 1.56% (82/5, 266), skin and appendages disorders such as rash and pruritus in 0.40% (21/5, 256), liver and biliary system disorders such as increased GOT and increased GPT in 0.27% (14/5, 266) and urinary system disorders such as increased BUN in 0.19% (10/5, 266) . No patients were judged by doctors as to have severe or serious adverse reactions. The adverse reactions were slight in 83.1%. In almost all the cases, the adverse reactions were recovered or resolved after Relifen^® tablet was discontinued or reduced in dosage or appropriately treated.
In 5, 192 cases assessed for efficacy in different categories of disease, efficacy rates were 46.4% (481/1, 037) in rheumatoid arthritis, 70.5% (1, 351/1, 917) in low back pain, 71.1% (413/581) in cervico-omo-brachial syndrome, 67.3% (230/342) in scapulohumeral periarthritis and 61.2% (800/1, 307) in osteoarthritis.
We submited the documents for the above-stated post-marketing surveillance to apply re-examination in June, 1900, and were informed of the results from the re-examination on March 3, 1999, to confirm that Relifen^® tablet (nabumetone) had the similar safety and efficacy as those initially approved.

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