Pathology of rheumatoid arthritis is characterized by lymphocyte and macrophage infiltration and subsequent proliferation of synovial fibroblasts. The proliferative synovial tissue is called pannus, which destroys cartilage and bones of the affected joints. Most of the previous studies to develop new therapeutic approaches addressed how the synovial lymphocytes and macrophages are activated. We attempted to reveal abnormality of cell cycle control of the synovial cells and found that cyclindependent kinase inhibitors p16INK4a and p21Cip1 are readily inducible in the rheumatoid synovial fibroblasts. These inhibitors negatively regulate cell cycle of the mature cells, and actually suppressed proliferation of the synovial fibroblasts when their genes were adenovirally transferred. In vivo gene delivery of these genes into the joints of animals affected with experimental RA models suppressed pathology of the arthritis. The results showed that induction of CDKI in the synovial tissues could be a new therapeutic approach to treatment of rheumatoid arthritis.

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Glucocorticoids are not only essential hormones to maintain homeostasis but also effective drugs for controlling inflammatory disorders. Glucocorticoids inhibit expression of proinflammatory genes such as cytokines, chemokines, and adhesion molecules. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR) . The GR is localized in the cytoplasm in the absence of hormonal ligand. Upon binding ligand, the GR dissociates from molecular chaperones such as heat shock proteins and translocates into the nucleus. The GR interacts with other transcription factors such as NF-κB and AP-1 which activate proinflammatory genes and inhibits inflammation through negative regulation of these transcription factors and/or competition with these transcription factors for association with coactivators. Therefore, nuclear translocation of the GR is an important step for glucocorticoid action and is controlled by nuclear localization signals within the GR molecule and various cellular factors. It is suggested that cellular oxidation-reduction (redox) status also regulates nuclear translocation of GR by targeting the cysteine within the NL1. We demonstrated that various functions of GR are regulated by redox status.
Taken together, it is important to understand the mechanisms of redox dependent regulation of GR function, to aid development of novel drugs and therapies for various disorders including inflammatory diseases.

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Phagocytes play a central role in the host defense system. We have previously reported that cofilin, an actin-and PIP₂-binding phosphoprotein, is dephosphorylated upon activation of phagocytes. To clarify the role of cofilin in the functions of phagocytes, we investigated the relationship between cofilin and phagocyte activation. In neutrophil-like HL-60 cells, the production of superoxide induced by opsonized zymosan (OZ) was enhanced at l pM and inhibited at 5 pM by okadaic acid (OA), a protein phosphatase inhibitor. Furthermore, OZ induced dephosphorylation and translocation to the plasma membrane regions of cofilin, which were also inhibited by OA at 5μM. In macrophage-like U 937 cells, both Herbimycin A, an inhibitor of Src family tyrosine kinase, and U 73122, an inhibitor of phospholipase C (PLC), inhibited OZ-induced superoxide production and phagocytosis as well as dephosphorylation and translocation of cofilin. Herbimycin A also inhibited the temporary increase of F-actin content, the decrease of intracellular pH, and tyrosine phosphorylation of p 110, p 50, p 34, and p 29, all of which were induced by OZ. In addition, as well as U 73122, Herbimycin A inhibited IP₃ production during cell activation by OZ. From these results, it was shown that the activation of phagocytes and the change on the condition of cofilin are significantly related. The signaling pathway from OZ stimulation to cell response including Src family tyrosine kinase and PLC is discussed.

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The effect of teprenone, a cytoprotective agent and rabeprazole, a proton pump inhibitor (PPI), in preventive mucosal damages caused by piroxicam was evaluated in a controlled prospective study in 30 rheumatic patients requiring NSAIDs. Piroxicam capsules at a clinical standard dose of 20 mg/day were administered in 30 patients for 2 weeks and 20 patients were randomly assigned to receive either rabeprazole 10 mg once daily or teprenone 3 times daily for 2 weeks, along with piroxicam. Gastric damage was slightly less tendency in teprenone group compared with the only administered piroxicam group. However, duodenal ulcers developed in 2 cases in both groups with no intergroup difference in preventive effect. Among 10 patients given 10 mg of rabeprazole along with piroxicam, there was a significantly lower incidence of development of gastroduodenal damage in rabeprazole administered group compared with patients given only piroxicam, which suggested that PPI is as effective in suppressing NSAID induced acute gastroduodenal lesions.

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A 48-year-old female presented a bleeding tendency due to thrombocytopenia (7000/μ1) in August 1990. She was diagnosed as having idiopathic thrombocytopenic purpura (ITP), and splenectomy was carried out in May, 1991. Her peripheral platelet count increased to the normal level after that, and she was followed up at our hospital regularly in healthy condition.
But, skin eruptions appeared transciently in August 1995, and a recurrent, persistent cough like chronic bronchitis bothered her from June 1996. She suffered from herpes zoster of the right trigeminal nerve in sudden, and had hospitalization in December 1998.
Her chest X-ray film presented the bilateral hilar lymphadenopathy on admission, so several further examinations were done. As results, she was proved to be a human T-cell leukemia virus-type I (HTLV-I) carrier, and biopsy spacimens of her left upper-lung established the diagnosis of sarcoidosis.
The clinical process of HTLV-I infection, ITP, and sarcoidosis in this case makes us take it into consideration that the pathophysiological mechanism of ITP might have a possible etiological relationship with HTLV-I infection, which can be responsible for the increased antiplatelet T helper lymphocyte reactivity in patients with ITP.

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Inhibition of the development of adjuvant arthritis (AA) in male LEW rats by a daily, oral dose of 0.3 mg/kg of methotrexate (MTX) was examined in terms of timing and duration of treatment. A complete suppression of AA development until day 21 was obtained by dosing from days 5 to 14 after CFA inoculation in the hind foot, as well as that from day 0 to day 18 throughout, while AA symptoms appeared in a dose-related manner as the daily doses decreased to 0.1 and 0.05 mg/kg. The same schedule of treatment also inhibited completely the onset of CP 20961-induced, AA-like polyarthritis in male LEW rats. The autopsy findings on the rats being free from AA development were nearly close to those from normal controls. However, their draining lymph nodes were found to be still much larger on day 21, and AA, even to a mild degree, developed late with a maximum on day 28. Dosing from days 5-9 delayed significantly AA onset for a few days followed by a rapid development of the disease, and in addition, decreased DTH responsiveness in skin and IL -2 production in cultured lymph node cells, both of which were determined by PPD stimulation on day 11. MTX had no effect on the time courses of both the primary and secondary swelling in the hind feet. From these results, it is concluded that MTX may act to delay onset time of AA, mainly by suppressing the progression of T-cell maturation and activation beginning from day 4 or 5, and secondarily by preventing any cross-talk between T-cells and macrophages, which occurs around day 10.

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IgG-rheumatoid factor (RF), IgM-RF, antidsDNA, anti-ssDNA, and anti-Sm antibody have been detected and have been thought to play an important role on pathogenesis of systemic lupus erythematosus (SLE) . MRL/MP-lpr/lpr (MRL/lpr) mice have been studied widely as experimental animal model for autoimmune disease. IgG-RF, IgM-RF and anti-ds DNA antibody, anti-ss DNA antibody and anti-Sm antibody were titrated by a one-step sandwich enzyme-linked immuno-sorbent assay (ELISA) system in the serum of MRL/ lpr mice. Titer of the autoantibodies was ranged from 4 to 1000 mU.
These results disclosed evidences that the new ELISA kits were useful to titrate IgG-RF, IgM-RF and anti-ds DNA antibody, anti-ss DNA antibody and anti-Sm antibody. The assay system could be employed to study on efficacy of therapeutic agents and to analyse pathoetiology of the autoimmune disease in mice.

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[in Japanese]

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We report here a case of Langerhans cell granulomatosis resembling so-called pulmonary eosinophilic granuloma. Patient was a 38 year-old male with chief complaints of fever and general fatigue, and also showed skin lesions with crust and ulcer of gingiva. Chest X-ray film in hospitalization showed diffuse abnormal shadows which were not detected two months before the admission. In both lung fields, diffuse multiple small cystic lesions with thin wall, small nodules and patchy lesions were also seen on chest computed tomography. Abnormal shadows were dominant in upper lung fields. No other involvement of organs including bones were found by garium and bone scintigraphies.
Biopsy specimens were obtained from transbronchial lung biopsy, skin and gingiva. Granuloma formation with Langerhans cells and eosinophils invasion were found in all biopsy specimens by hematoxylin-eosin staining and immunostaining against the S-100 protein. On the basis of these findings, we gave the preferable diagnosis of Langerhans cell granulomatosis rather than pulmonary eosinophilic granuloma, because the patient showed systemic involvement. However, main organ involved was the lung and the clinical findings were looked like pulmonary eosinophilic granuloma as a localized disease. Interestingly, without specific treatment excluding smoking cessation, clinical symptoms and chest X-ray abnormalities improved spontaneously in this case.

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