Recent studies have demonstrated that there are two isozymes of COX (PGHS), COX-1 and COX-2. The roles of COX-1 and COX-2 in PG synthesis under physiological and pathological situation remain unclear, though it has been recognized that COX-1 produces PGI₂ in endothelium, TXA₂ in platelets, and PGE₂ in gastric mucosa. In this paper, we will demonstrate the regulation of gene expression and activity in COX-1, and the characteristics of COX-1 protein and also discuss the physiological meanings of COX-1. In intact cells, endogenous arachidonic acid is not converted by COX-1, but exclusively converted by COX-2. The reason will be demonstrated that the Km value for arachidonic acid in COX-1 is different from that in COX-2 in intact cells. This means COX-1 dose not act under physiological conditions, and both COX-1 and COX-2 are timed to act complementary to each other under pathological conditions.

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Proliferation of synovial fibroblasts is regulated by several kinds of cytokines. This review summarizes the effects of cytokines on synoviocyte proliferation. Signal transduction mechanisms for synovial proliferation through Ras pathway is also discussed.

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The indications for morphine in palliative cancer care are severe pain, dyspnea (tachypnea), cough and diarrhea. The use of morphine is the mainstay in managing cancer pain, because it is simple to administer and, when properly used, it is very effective in the majority of cancer patients with pain. Since the WHO Method for Relief of Cancer Pain was published in 1986, there has been an increasing global awareness of the effective use of morphine in cancer pain management. It reflects a more than ten-fold increase in the medical use of morphine in Japan during the past ten years, but the current annual consumption per capita in Japan is less than one-tenth of that in UK and some other developed countries. This means that, while educational approach has been reinforced in recent years, there is still widespread lack of the latest knowledge about the use of morphine among the health care workers in Japan. They should be taught more about the basic skills and knowledge in the latest cancer pain management, such as evaluation of the pain, the five key concepts in analgesic drug use (by mouth, by the ladder, for the individual, by the clock and attention detail), the concept of total pain and others. Pain relief is a realistic target for the majority of cancer patients and much helps improve their quality of life.

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Macrophages play a key role in inflammatory reactions and immune reactions through releasing a variety of inflammatory mediators, such as prostanoids, superox-ide anions, and monokines. Macrophage migration inhibitory factor (MIF), one of the monokines, was originally discovered as a T lymphocyte-derived cytokine inhibiting migration of macrophages out of capillary tubes. Recently, Northern blot analysis indicated that the MIF mRNA was expressed in a wide variety of organs, including the brain, kidney, and liver. From the available data on MIF, it is considered that the protein is associated not only with immune responses but also with cell growth and differentiation during wound repair and carcinogenesis. On the other hand, vitamin E is recently noticed to play an important role as an antioxidant and moreover in immune responses, including protection against infections and carcino-gens beyond antioxidant functions. In order to clarify the possible role of vitamin E on the modulation of macrophages, we investigated the effect of vitamin E on MIF production in macrophages as stimulated with various agents. Intraperitoneal injec-tions of vitamin E (5 mg per rat) for 6 successive days resulted in a significant increase of α-tocopherol content in peritoneal macrophages. Vitamin E-treated rats showed 478.3±90.7 ng/l0⁶cells, whereas control rats showed 1.5±0.5 ng/10⁶cells. MIF secretion from control macrophages increased in response to calcium ionophore A23187 and LPS. However, increase of MIF was significantly suppressed in vitamin E-treated macrophages compared with that of control macrophages. From these results, it is suggested that vitamin E plays a pivotal role within the cytokine network in various pathophysiological states.

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Mast cells have been regarded as one of the most important effector cells in IgE-dependent allergic response. Recently the heterogeneity of mast cells in localization and species have been recognized. However, whether anti-allergic drugs possess inhibitory effects on histamine release from human mast cells still remains uncertain. Therefore, in the present study, effects of anti-allergic drugs on histamine release from human mast cells, which were derived by the culture of cord blood cells with 80 ng/ml recombinant human stem cell factor and 50 ng/ml interleukin 6. The human cultured mast cells presented functional IgE receptors on their cell surfaces and were effectively stimulated to release histamine in dose-dependent and time-dependent manners of anti-IgE antibody. Anti-allergic drugs, such as azelastine, ketotifen, and emedastin, were able to inhibit histamine release from the human mast cells in dose-dependent manners. Immunosuppressive agent, cyclosporin A, and flavonoid, quercetin, also showed inhibitory effects on the histamine release from the human cultured mast cells.

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T lymphocytes play a pivotal role in the pathogenesis of atopic dermatitis (AD) . Th2-skewing immunologic balance is commonly seen in patients with AD. Drugs or modalities that act on T cells for the treatment of AD can be divided into three categories: (1) immunosuppressants that inhibit transcription for cytokines, including cyclosporine A and FK506 (mainly the former is used orally and the latter topically) ; (2) Th2-inhibitory drugs/modalities, such as interferon-γ, some antiallergics, some Chinese-Japanese herbal medicine, and psoralen and ultraviolet A (PUVA) therapy; and (3) antigen-presenting cell-inhibitory drugs leading to T-cell inhibition, such as cyclosporine A and macrolides including FK506 and roxithromycin. These drugs/modalities are different from each other in the therapeutic efficacy and the intensity of adverse effects. For example, cyclosporine A and FK506 are highly efficacious but may evoke strong side effects. Since the severity of AD lesions varies from patient to patient, these drugs/modalities should be chozen in consideration of the diseases activity and tolerance in each patient.

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