Cell adhesion is a fundamental biologic process in the life of multicellular organisms. β1 integrins are heterodimeric glycoproteins, and function primarily as cell surface receptors for extracellular matrix proteins (ECM) . Interaction of cells with ECM via β1 integrins results in a change in cell behavior including mobility, growth, differentiation. This implies that β1 integrins may be capable of transmit-ting signals into the interior of cells. However, little has been known about signals generated by the binding of cells with ECM. Recently, we and others have shown that engagement of β1 integrins induced increased tyrosine phosphorylation of 105-130 kDa proteins in a number of cell types. One of these proteins was shown to be identical with pp 125^FAK, a newly identified cytoplasmic protein tyrosine kinase. pp 125^FAKis specifically localized at focal adhesions, and highly tyrosine phosphorylated after the ligation of integrins with their ligands or antibodies.
These findings strongly suggest that pp 125^FAKacts as a signaling molecule responsible for the integrin-dependent formation of focal adhesions. pp 125^FAKcan also be activated by cell transformation with p 60^v-srcor by mitogenic neuropeptides including bombesin, vasopressin and endothelin. Thus, pp 125^FAK may be a key regulatory molecule connecting cell adhesion, transformation, and growth. In this review, we summarize recent progress in the research of β1 integrins, especially focusing on signal transduction pathways.

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Acute lung injury is known as ARDS, wet lung syndrome, Da Nang lung and capillary leak syndrome. The cause of acute lung injury are aspiration pneumonia, viral and bacterial pneumonia, toxic gas inhalation and pulmonary thromboembolism. Alveolar macrophages are activated by various exogeneous stimuli and various chemical mediators including PGE₂, PGI₂, LTB₄, LTC₄, LTD₄, 5-HETE and TxB₂are released. Recruitment of neutrophils to pulmonary vascular beds is induced by LTB₄, IL-7, complement C5a and PAF released from alveolar macrophages. Neutrophils adhered to the inner surface of pulmonary vascular beds induced by adhesion molecules, then release LTB₄, elastase, PAF and free radicals. These substances injure lung tissues and acute lung injury occurs.

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Under opsonized zymosan (OZ) stimulation, the cypridinaluciferin analog dependent chemiluminescence (MCLA-CL) of neutrophils (PMNs) shows a different luminescence pattern with and without infection. The noninfected PMN shows the same luminescence pattern as with infection, when primed by tumor necrosis factor (TNF), f-methi-onyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) . From these findings, it is considered that the PMNs when infected, is primed by an increasing number of various mediators.

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We investigated the production of tumor necrosis factor-α, interleukin-6 and interferon-γ by peripheral blood mononuclear cells (PBMCs) of patients with hepatitis C virus (HCV) infection during interferon-α treatment. Studies were undertaken on 12 patients with chronic active hepatitis (CAH), 8 patients with chronic persistent hepatitis (CPH) and 10 healthy controls. Enzyme-linked immunosorvent assay (ELISA) was used to detect each cytokine in the culture media of 24 hours. Phyto-hemagglutinin (PHA) stimurated PBMCs. Before IFN-α treatment, TNF-α production by PBMCs was higher in CAH and CPH patients than that of healthy controls. There was a corelation between serum levels of alanine aminotransferase (ALT) and TNF-α production.
After IFN-α treatment, TNF-α production was significantly increased in both CAH and CPH patients. Before IFN-α treatment, IL-6 production by PBMCs from patients with CAH and CPH was not significantly higher than that of controls. However, production of IL-6 was significantly increased after IFN-α treatment. IFN-γ production by PBMCs was scattered and was not assosiated with CAH, CPH and controls.
After IFN-α treatment, those productions were increased in some patients, but the others were not responded to IFN-α treatment. The nature of these immunostimulatory effects were not fully understood, though these findings suggest that IFN-α treatment may induce some cytokines essential to an antiviral immunoresponse in chronic hepatitis patients with HCV infection.

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Rheumatoid synovial tissue produces excessive amounts of interleukin-6 (IL-6), which contributes to the immunopathogenesis of rheumatoid arthritis (RA) . In this study we assessed the effect of KE-298, a newly developed anti-rheumatic drug, and its metabolite KE-758 (M-1, deacetylated form) on IL-6 production by synovial fibroblast (SF) . Both KE-298 (25-100μg/ml) and KE-758 (25-100μg/ml) inhibited spontaneous and IL-1 stimulated IL-6 production by SF (spontaneous: KE-298 20%, KE-758 51%, IL-1 stimulated: KE-298 42%, KE-758 47%) . Northern blot analysis showed that KE-758 inhibited IL-1 stimulated IL-6 mRNA expression in SF. To elucidate the mechanism of the inhibitory effects, IL-1β binding assay using SF was performed. ¹²⁵I-IL-1β binding to SF was inhibited by KE-298 or KE-758 at the concentration of 50-200μg/ml. These data indicate that KE-298 and KE-758 would provide their anti-arthritogenic actions by way of intervening the cytokine network of RA.

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The involvement of heat shock protein (hsp) in the pathogenesis of RA has been implied, however, the precise mechanism is still unknown. We analyzed the individual data of antibody level to r-hsp 65 in comparison with the level to the crude mycobacterium extract (MT-WE) . The high antibody level to hsp65 with low level to MT-WE has been specifically observed in RA.
However, the sera included antibody to r-hsp 65 did not react with human hsp obtained from heat shocked human cells.
This suggest that the antibody may direct to nonconserved region of mycobacterial hsp65. On the contrary, much more human hsp72/73 was expres-sed on unstimulated rheumatoid synovial tissue cells than peripheral blood mononuclear cells. These findings imply the importance of hsp in the pathogenesis of RA, though the mechanism may be more complicated than expected.

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A topical NSAID prodrug preparation has not previously been successfully developed because penetration through the skin and activation in the local tissue of prodrug, and a subsequent pharmacological effect could not be obtained. We devised the base for the ointment and cream forms indomethacin farnesil (IND-F, a NSAID prodrug) to include isopropylalcohol, polyalcohol, isotridecyl-myristate, diethyl sebacate, polyethyleneglycol, diisopropanolamine, oxybenzone, carboxy-vinylpolymer and purified water.
The percutaneous absorption of IND-F was confirmed by an increase in the plasma concentration of indomethacin (IND) at 2, 8, and 24 hrs after IND-F application (1.64 mg) to hairless rats. In a rat model of adjuvant arthritis, IND-F ointment and cream produced signicant inhibition of foot edema when compared to the base alone (P<0.01) . In a rat cotton pellet model, there was also significant inhi-bition of the growth of granulation tissue in the IND-F-treated group when compared to the basetreated group (P<0.05) .The clinical efficiency of IND-F ointment was also evaluated in 14 patients with rheumatoid arthritis. Significant clinical improvement was observed, including a decrease in the number of painful joints, joint swelling, morning stiffness, and the PIP ring number.
These results suggest that this new topical NSAID prodrug may be useful in the treatment of rheumatoid arthritis.

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We newly prepared topical formulation for the mycophenolic acid in this study. Our preparation was effective enough to reduce the experimental allergic contact dermatitis induced by DNFB. Evaluation of efficacy of mycophenolic acid cream was performed as visual estimation on skin reaction and observation of tissues under the light microscope at 1, 2, or 3 days after the treatment. Skin damages of guineapigs treated with mycophenolic acid topical preparation were significantly improved compared to the group treated with vehicle only. This effect was continued up to 3 days. The degree of efficacy was better than betamethazone, especially in the early stage of treatment. Light microscope observation also supported these results. And it suggested that effect of mycophenolic acid cream would reach to dermis and epidermis layer. This novel topical preparetion of mycophenolic acid could be promising regime for the treatment of psoriasis and atopic dermatitis.

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It was demonstrated that the oriental medication‘Tsu-hi-rei’is clinically useful and effective in treatment of patients with rheumatoid arthritis in China. This effect was supposed to be due to immunomodulation by decreasing of rheumatoid factor and immunoglobulin levels and various parameters of inflammation.
So a basic experiment to investigate its mechanism of action was scheduled by using collageninduced arthritis in DBA/1J mice. From 4 weeks after booster injection of type II collagen, “Tsu-hi-rei”and western medication such as indomethacin and an immunomodulator were given, and their effects were compared by clinical observation, X-ray findings and pathologic examination. Anti-collagen antibody was also measured in each treatment group by ELISA.
“Tsu-hi-rei”showed suppression of collagen-induced arthritis in frequency and severity. The soft X-ray study revealed decreased bone-destruction and, in sera, titers of anticollagen antibody were lower than in controls.
These data suggest that“Tsu-hi-rei”has an antiinflammatory and immunosuppressive effect on collagen-induced arthritis.

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