In human umbilical vein endothelial cells, treatment with tumor necrosis factor (TNF) -α stimulated the production of cellassociated interleukin (IL) -1α. Combined treatment of human umbilical vein endothelial cells with TNF-α and the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed the TNF-α-induced IL-1α production. However, concentrations of 6-keto-prostaglandin F_1α in the conditioned medium were increased to a greater extent by combined treatment with TNF-α and TPA than by single treatment with TNF-α or TPA. Pretreatment with TPA for 15 min was enough to suppress the TNF-α-induced IL-1α production. Pretreatment for 15 min with other PKC activators such as aplysiatoxin (AT) or teleocidin (TC), also inhibited the TNF-α-induced IL-1α production. Stimulation of cell-associated IL-1α production by IL-1β or lipopolysaccharide (LPS) was also inhibited by treatment with the PKC activator TPA, AT or TC. However, treatment with the protein kinase inhibitor H-7 did not block the inhibitory effect of TPA, AT or TC on the cellassociated IL-1α production stimulated by TNF-α, IL-1β or LPS, although the PKC activator induced stimulation of 6-keto-prostaglandin F_1α production was counteracted by H-7 treatment. These findings indicate that the production of cell-associated IL-1α stimulat-ed by TNF-α, IL-1β or LPS is inhibited by these PKC activators, but the inhibition by such PKC activators of IL-1α production is not due to PKC-dependent mechanism.
To further confirm this notion, effects of these drugs on IL-1 production by other cells were examined. In human pulmonary artery endothelial cells, these PKC activators inhibited cell-associated IL-1α production stimulated by TNF-α, IL-1β or LPS, and this inhibitory effect was not counteracted by the PKC inhibitor H-7 or staurosporine. In contrast, in human epithelial cell line NCI-H₂₉₂, these PKC activators further enhanced LPS-induced IL-1α production. In addition, IL-1β production by human dermal fibroblasts and human promyelocytic leukemia cell line HL-60 stimulated by LPS or TNF-α was enhanced by these PKC activators. These results suggest that the suppression of IL-1α production by these PKC activators is a specific event to vascular endothelial cells.

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A single peritoneal injection of cell wall extract from Lactobacillus casei (LCWE) in mice can induce acute cardiac angitis mimicking that observed in patients with Kawasaki disease (KD) . Several proinflammatory cytokines play an essential role in the generation of vasculitis in KD and mice. Many reports show that highdose administration of human immunoglobulins (IVIG) prevents progressing coronary aneurysms in KD. IVIG contains the antibodies against some proinflammatory cytokines, to neutralize their activity. However, the central mechanism of therapeutic efficacy remains unclear.
The present paper describes the suppressive effect of dexamethasone and mouse IgG (mIgG) on LCWE-induced vasculitis in mice. The mIgG was sterilely purified from sera of retired mice. A one shot intravenous treatment of mIgG (1 mg/lg of body weight) with prior (4 hr before) or simultaneous injection of LCWE significantly suppressed the generation of cardioangitis in mice. Anti-IL-1α antibody could not be detected in the mIgG used in this study. The administration of dexamethasone (4 μg/1 g of body weight) with LCWE could also inhibit the generation of vasculitis. We discuss the suppressive effect of mIgG and dexamethasone on LCWE induced cardioangitis in mice.

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To investigate the mechanism of improvements in the symptoms of rheumatoid arthritis (RA) induced by an extracorporeal granulotrap column (G-1), an ex vivo study was undertaken on peripheral blood from RA patients while being treated with the G-1. Our focus was on the modulations of granulocytes and monocytes, but also on T cell function as well during or after completion of G-1 therapy. The G-1 column selectively trapped granulocytes and monocytes from peripheral blood with a trapping efficiency of about 40%.
This resulted in a decrease in inflammatory leukocytes in the systemic blood during apheresis (p<0.05, n=14) . The production of TNF-α, IL-6 and IL-8 was also significantly decreased in blood stimulated by LPS at post column by compared with pre perfusion (p<0.02, n=9) . IFN-γproduction by T cells stimulated with anti CD3 MoAb showed a modest but significant decrease during apheresis (p<0.05, n=8) . Additionally, IL-1β production capacity of mononuclear cells stimulated with LPS was strikingly suppressed in studies of 6 patients (p<0.05) after the initiation of G-1; the effect was sustained for up to 2 weeks after completion of G-1 therapy.
The results suggest that the G-1 column, in addition to trapping fraction of granulocytes and monocytes, also produces extracorporeal immunomodulation.

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Polymorphonuclear leukocytes (PMN) play an important role in development of inflammation. In the clinical field, non-steroidal anti-inflammation drugs (NSAID), such as proglumethacin maleate, were used to theraphy with arthritis. In this study, we investigated the effects of NSAIDs on superoxide generation of human PMN from synovial fluid.
On the PMNs from synovial fluid of rheumatoid arthritis (RA) patients, proglumethacin maleate significantly inhibited the superoxide generation by phorbol 12-myristate 13-acetate (PMA) . The rate and maximum amount of superoxide generation of PMNs were reduced to 12.72±6.32% and 24.23±9.44%, respectively. The other NSAIDs, Indomethacin farnesil, diclofenac sodium and loxoprofen sodium, were also tended to inhibit the superoxide generation by PMA, but not significantly. Indomethacin farnesil, diclofenac sodium and loxoprofen sodium reduced the rate of superoxide generation to 55.88±5.58%, 41.17±2.36% and 45.24±1.77%, respectively. Proglumethacin maleate also strongly inhibited the superoxide generation of PMNs from patients of osteoarthritis (OA), but other NSAIDs did not. The rate and maximum amount of superoxide generation of PMNs from OA patients were reduced by proglumethacin maleate to 21.20±2.79% and 32.36±10.09%, respectively. Indomethacin which is active metabolite of proglumethacin maleate for NSAID did not inhibit the superoxide generation of PMNs from RA and OA patients.
These result indicated that proglumethacin maleate have inhibitory action to superoxide generation of PMNs which is not NSAID's action. This inhibition of superoxide generation of PMNs may be one of the anti-inflammatory mechanisms of proglumethacin maleate.

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The chronic fatigue syndrome (CFS) is a condition of unknown etiology, characterized by an extreme fatigue that is exacerbated by minimal physical activity. Immunological abonormality is prevalent in patients with CFS (e. g. abnormal functions of natural killer cell, macrophage, and lymphocyte) . However, in our knowledge, no study has been reported about neutrophil function, so that we have investigated a neutrophil bactericidal function, luminol-dependent chemiluminescence (L-DCL), in a 24-years old female with CFS. L-DCL under whole blood condition was apparently increased, while L-DCL from separated neutrophils was in normal range. A combination therapy with vitamin C, vitamin E, and eicosapentanoic acid, those are known to be antioxidant drugs and to inhibit a generation of oxygen derived free radicals from neutrophils, apparently improved her symptoms and L-DCL under whole blood condition. These data suggest that symptoms of CFS may be partially caused by inflammatory mediators such as oxygen derived free radicals and the combination therapy may be useful to improve the symptoms of CFS. It may be possible that the measurement of neutrophil bactericidal function is available to evaluate the condition of CFS.

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We investigated the effect of far infrared ray (4-14 μm-or growth ray-) emitting stones or products on several inflammatory parameters of human leukocytes, leukemia cell lines, neoplasma and RA patients. [Ca²⁺] i, chemotaxis, phagocytosis and O^-₂ generation by neutrophils, blastogenesis to PHA by lymphocytes were significantly increased 60 min after the test tubes containing neutrophils and lymphocytes were surrounded with these stones and products. [Ca²⁺] i was slightly increased in HL60, unchanged in ML1 and decreased in K562, respectively. The growth of Sarcoma 180 cells or B-16 melanoma transplanted from tumor mice was inhibited by covering the back of the mice with clothes which were produced from the powder of the crushed stones or ceramics. Lipid peroxidation was also decreased by surrounding the bottom of test tubes with test materials. Among the four test materials, SGES showed the marked effect on the above parameters, especially on lipid peroxidation. HgC1₂-induced hepatitis in rat was well improved by the administration of micropowder of the crushed SGES. Eighty five RA patients at exacerbated stages were also administered micro-powder of SGES and subjected for taking bath which is produced from SGES. In about half of the patients, their clinical symptoms and/or the levels of CRP and ESR were improved. Their serum lipid peroxide levels were decreased. Since iatrogenic disorders have recently been social problem, not chemically synthetic, but natural far infrared ray emitting stones or products without any side effect may be recommended for medical treatment.

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1. In order to determine the optimal oral dose of methotrexate for the treatment of Japanese patients suffered from chronic rheumatoid arthritis (RA), a multi-insti-tutional double-blind study was performed using three different doses (2, 6 and 9 mg/week), each of which was divided into three rations and administered far twelve weeks.
2. The overall improvement ratios at the end of study for each dosing groups were as follows; 26.9% (14/52) in 2 mg/week dosing group, 60.4% (32/53) in 6 mg/week dosing group and 64.4% (29/45) in 9 mg/week dosing group. There was no significant statistical difference between the ratios of 6 and 9 mg/week dosing groups. Although, the latter dosing group seemed to have gained better results than the former dosing group.
3. The respective general safety ratios for 2, 6 and 9 mg/week dosing groups were 72.7% (46/66), 64.7% (44/68) and 64.6% (42/65) . These results indicated no significant statistical difference among these groups ; The general safety ratio of 6 and 9 mg/week dosing groups leveled each other, whereas that of 2 nag/week dosing group appeared to be most favorable.
4. The incidence ratios of the adverse side effects were 10.6% (7/66; 16 cases) in 2 mg/week dosing group, 17.6% (12/68; 24 cases) in 6 mg/week dosing group, and 12.3% (8/65: 12 cases) in 9 mg/week dosing group, indicating that no significant statistical difference exists among these groups. As a severe adverse symptoms, one case of loss of consciousness was observed in 2 mg/week dosing group, one case of vomiting accompanied with diarrhea which required hospitalization was observed in 6 mg/week dosing group, and one case of interstitial pneumonia was observed in 9 mg/week dosing group.
5. The incidence ratios of abnormalities in the clinical chemistry were 23.4% (15/64 ; 7 cases) in 2 mg/week dosing group, 23.8; (15/63 ; 33 cases) in 6 nag/week dosing group and 36.7% (22/60 54 cases) in 9 nag/week dosing group, indicating that no significant statistical difference exists between these groups despite of the highest ratio observed at 9 mg/week dosing group. Decrease in leukocyte and platelet counts were detected in 9 mg/week dosing group only.
6. The usefulness (benefits for patients) ratios at the end of study for each dosing groups were as follows: 19.6% (11/56) in 2 nag/week dosing group, 45.2% (28/62) in 6mg/week dosing group and 38.9% (21/54) in 9 mg/week dosing group. Thus, the statistically significant difference in the usefulness ratios was observed between the 2 and 6 mg/week dosing group only.
7. On the basis of the above described efficacy and safety assessment of methotrexate, the optimal dose for Japanese patients with RA is assumed to be 6 mg/week. In reference to previous reports on Japanese patients, possible oral doses for clinical practice in RA were regarded to be ranged from 4 to rug/week. However, the maximal dose of 9 mg/week should be adopted under meticulous care of the adverse reactions, and only when neither the lower doses elicited sufficient effects nor adverse side effects is observed.

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The effect of misoprostol (Cytotec^®), an cytoprotective agent, in preventing mucosal damage caused by piroxicam and ampiroxicam was evaluated in 20 patients requiring NSAID. Patients with normal endoscopic findings were administered both misoprostol 600μg and ampiroxicam 27 mg for 2 weeks. Gastroduodenal mucosal damage was significantly less in the misoprostol administered group than the only ampiroxicam administered group (p<0.05) . There was a significantly lower incidence of development of gastroduodenal mucosal damage in the non-habit of drinking group than the group of habit of drinking. As to the preferential site for the development of thesee lesions, the commonest site was the duodenum. Against lesions developed in the duodenal, significantly higher prophylactic effect was observed for the misoprostol administered group.
It is considered from these results that misoprostol exists a highly prophylactic effect against piroxicam and ampiroxicam induced upper gastrointestinal mucosal damage.

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