Castleman's disease is a syndrome charaterized by lymph node hyperplasia with plasma cell infiltration, fever, anemia, hyper-γ-globulinemia, and an increase in the plasma level of acute phase proteins. We have demonstrated that the hyperproduction of IL-6 in germinal centers of hyperplastic lymph nodes of this disease was the main pathogenic cause in Castleman's disease. Thus, the blockade of IL-6 signal transduction may be therapeutically effective for the disease. For this purpose, humanized anti IL-6 receptor antibody (rhPM-1) was generated from mouse anti IL-6 receptor antibody, and its therapeutic efficacy has been examined in seven patients with plasma cell type of Castleman's disease.
After administration of rhPM-1 to the patients, inflammatory symptoms, such as low grade fever and general fatigue, and abnormal findings of anemia, thrombocytosis, hyper-γ-globulinemia, hypoalbuminemia and elevation of acute phase proteins have been improved in the patients. These evidences are indicated that the blockade of IL-6 signal transduction, such as humanized anti IL-6 receptor antibody, can be a new therapeutic agent based on the pathological significance of IL-6 in Castleman's disease.

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The blocking effect of curdlan sulfate (CRDS) on human immunodeficiency virus (HIV) infection has been thought to be related to inhibition of the binding of HIV-1 envelope glycoprotein (gp120) and CD4 molecules. However, recent reports have indicated that blocking the binding of gpl20 to CD4 by CRDS only makes a small contribution to the inhibition of HIV-1 infection. We report and discuss here that the effect of CRDS on the production of β-chemokines and cytokines might be important in the inhibition of HIV-1 infection, in addition to interference with the binding of gp120 to CD4⁺ cells. In other anti-HIV agents, these regulatory effects on chemo-kines and cytokines production may play an important role in the inhibition of HIV infection.

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Periodontitis results in degradation of periodontal connective tissue and subsequent detachment of the tissue to teeth, and is the main cause of teeth loss. Preventive and therapeutic methods, however, have not been established against the dental disease. Porphyromonas gingivalis is the major causative bacterium of adult periodontitis and the bacterial“trypsin-like”proteinases attract attention as virulence factors. As the “trypsin-like”proteinases, two arginine-specific (gingipain R) (50 kDa and 95 kDa) and one lysine-specific (gingipain K) (105 kDa) cysteine proteinases are purified from the bacterium, the larger proteinases being complexed with adhesin/hemagglutinin domains. Gingipain pathogenic functions were introduced, especially on vascular permeability enhancement induction through prekallikrein activation and subsequent release of bradykinin, fibrinogen degradation and thrombin production through factor X activation. These gingipain functions are closely associated with gingival crevicular fluid production, neutrophil accumulation, bleed-ing tendency, connective tissue and alveolar bone degradation, etc. at periodontitis sites. Thus, gingipains are likely to play a crucial role in the pathogenesis and development of periodontitis, therefore, possible targets in periodontitis control. Immunization using gingipains or their fragments and gingipain specific inhibitor administration will be available for periodontitis prevention and therapy.

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Transforming growth factor (TGF) -βs, activins/inhibins, and bone morphogenetic proteins (BMPs) form the TGF-β superfamily, members of which are involved in a wide variety of biological phenomena including inflammation. Signals of the TGF-β superfamily are propagated by two types of serine/threonine kinase receptors across the cell membrane. Recent discovery of the Smad proteins has led to the elucidation of intracellular signal transduction of the TGF-β superfamily. Three classes of Smads have been identified. Class I Smads are directly phosphorylated by the type I receptors and mediate receptor-specific signals. Smad4, the only vertebrate class II Smad identified, acts as a common partner of the class I Smads by forming heteromeric complexes. Class III Smads inhibit signals by interfering with the phosphorylation of the class I Smads. Complexes of the class I and class II Smads work as transcriptional activators in the nucleus following translocation from the cytoplasm. Furthermore, signals of the TGF-β superfamily may have cross-talks with other signaling pathways via Smad proteins. Elucidation of the Smad functions will help to understand the molecular basis of the inflammatory processes.

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Urticaria is characterized by wheal and flare, which usually disappear within several hours. However, there are some cases with severe and/or prolonged eruptions lasting more than 24 hours and resistant to treatments by ordinary histamine antagonists. Histology of such cases accompanies various cell infiltrations, such as eosinophils and neutrophils. In order to know the mechanism of such infiltrations, we studied the release of chemotactic activities from skin slices for neutrophils and eosinophils. The factor was identified with LTB4 by HPLC analysis and released either by antigens or substance P. Moreover, studies with skin chambers on patients with chronic urticaria revealed spontaneous release of substance P, suggesting the involvement of neuropeptides in the pathogenesis of chronic urticaria. Incubation of skin slices with dexamethasone scarcely inhibited histamine release, but almost abolished release of LTB4 in response to antigens. Recently-developed histamine H₁-antagonists, called anti-allergic drugs, inhibited both degranulation and TNFα releases from rat mast cell (RBL-2H3) line, but concentrations required to inhibit TNFα release was about one tenth of those to inhibit degranulation. Inhibition of LTB4 and TNFα from mast cells may partially account for clinical efficacy of corticosteroids and some anti-allergic drugs for treatment of chronic idiopathic urticaria.

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Mast cells have been recognized as one of the most important effector cells in IgE-dependent allergic reactions. Recently, the relationship between mast cells and fibroblasts has been indicated in the process of fibrotic conditions. Actually the number of mast cells is increased in the specimens obtained from fibrotic diseases, such as the involved skin of keloid and the forearm in an early stage of systemic sclerosis. Our studies showed that activation of human mast cells, which were generated from cord blood in the presence of stem cell factor and interleukin 6, increased [³H] thymidine incorporation into human fibroblasts, indicating that the mast cells possess a proliferating activity on fibroblasts. Tryptase has been indicated as one of the fibrogenic factors. In addition, our studies showed that cord blood-derived human cultured mast cells constitutively express mRNA for transforming growth factor β₁, which can be involved in fibrotic conditions. These data indicate that mast cell is now being recognized to play new roles in allergic inflammation.

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Indometacin farnesil (IMF) is a prodrug of indomethacin (IND) designed to reduce the occurrence of side-effects by esterification of the carboxyl group on IND with farnesol. Previous studies have shown that IMF has characteristics of disease modifying anti-rheumatic drug in that it has a component of slow acting effect in the treatment of rheumatoid arthritis patients. We therefore examined the effects of IMF on human B cells. Special attention was paid to the synergistic effects of IMF and methotrexate (MTX) . Ig production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. At pharmacologically attainable concentrations, IMF as well as MTX, but not IND, suppressed the production of IgM and IgG. Of note, IMF, but not IND, showed synergistic suppressive effects on the B cell Ig production in the presence of low concentrations of MTX. Thus, IMF, but not IND, significantly enhanced the suppression of Ig production mediated by MTX.
These results indicate that IMF suppresses the human B cell functions by a different mechanism from that of MTX. Moreover, the data suggest that IMF may enhance the anti-rheumatic effects of MTX and therefore may have more beneficial effects than IND in the treatment of patients with rheumatoid arthritis.

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Daunorubicin (DNR), one of the chemotherapeutic agents for the treatment of leukemia, is known to induce apoptotic cell death of leukemia cells. Apoptosis of leukemia cells in vivo accompanies phagocytic response by macrophages, which is now known to produce various mediators including PGE₂. In the present study, we studied the effect of PGE₁, a PGE₂ analog, on the DNR-induced apoptosis of human leukemia cell line, U937.
PGE₁ itself had no effect on the cell cycle of U937, but it inhibited DNR-induced apoptosis in a dose dependent manner. This inhibitory effect was mimicked by a membrane-permeable cAMP analog, db-cAMP, and forskolin. Furthermore, pretreatment of U937 cells with H-89, a protein kinase A inhibitor, reversed the inhibiting effect of PGE₁. When co-cultured with LPS-activated peripheral blood monocytes, DNR-treated U937 cells showed less apoptosis, which was augmented by inhibiting endogenous production of PGE₂ from LPS-activated monocytes when they are cultured with indomethacin. Therefore, it suggested that PGE₁ inhibited DNR-induced apoptosis through activated cAMP, PKA signaling pathway. These results clearly show that PGE₁ inhibition of DNR-induced apoptosis of U937 is mediated by cAMP/PKA signaling pathway and that endogenous production of PGE₂ by macrophages, which eliminate apoptotic cells by phagocytosis in vivo, attenuates DNR-induced apoptosis of U937 cells. The present study suggests that administration of cyclooxygenase inhibitor, such as indomethacin, enhances chemotherapeutic effect of DNR-induced apoptosis of leukemia cells.

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