Glucocorticoids are produced in the adrenal cortex under the strict control of the hypothalamus-pituitary-adrenal axis and exert a variety of biological actions including the regulation of glucose and lipid metabolism, electrolyte balance, and modulation of the immune, cardiovascular, and central nervous system. Pharmacologically, glucocorticoids are estimated to be used long-term by 0.5-1% of the general population and up to 2.5% of older adults. Despite the established role of glucocorticoids in controlling short-term inflammation, and despite emerging evidence supporting a disease-modifying role in various autoimmune disorders, concern for adverse events associated with glucocorticoids often limits their use. The glucocorticoid compounds bind the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily, and elicit their pharmacological actions. Recent progress in molecular biology of the GR has extended our understanding of their mechanism of action, however, the molecular basis for the side effects have not been fully clarified. Indeed, dissociation of their therapeutic effects and adverse reactions is still one of the most challenging clinical issues to be solved.
In this lecture, I will focus on the recent understanding of the molecular mechanism of glucocorticoid action and our recent work with ursodeoxycholic acid and cortivazol and discuss rationale to develop novel glucocorticoid-like compounds.

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Fibrosis is a common pathway resulting in organ failure. Renal fibrosis is a progressive and potentially lethal disease caused by diverse clinical entities. The degree of renal fibrosis well correlates with the prognosis of renal diseases independent of their etiologies. Fibrocytes are peculiar circulating cells that share markers of leukocytes as well as mesenchymal cells. A considerable number of fibrocytes dual positive for CD45 and type I collagen or CD34 and type I collagen infiltrated the interstitium along with the progression of fibrosis in an experimental murine renal fibrosis model. Most fibrocytes in the kidneys were positive for CCR7. In addition, a ligand for CCR7, secondary lymphoid tissue chemokine (SLC/CCL21) co-localized with high endothelial venule-like vessels in fibrotic kidneys. CCL21/CCR7 blockade reduced the number of infiltrating fibrocytes as well as the extent of renal fibrosis, which was confirmed by a decrease in renal transcripts of pro α1 chain of type I collagen and transforming growth factor-β₁. These findings suggest that CCL21/CCR7 signaling contributes to the progressive renal fibrosis through the regulation of fibrocytes.

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Overturning the long-held dogma that the central nervous system (CNS) of adult mammals never regenerates, recent evidence has revealed that neural stem cells continually generate new neurons in two regions of the adult mammalian CNS: the hippocampus and the olfactory bulb. Although adult neurogenesis is limited outside these two regions, accumulating evidence indicates the existence of neural progenitors even in non-neurogenic regions. In the adult mammalian retina, Müller glia generate new retinal neurons in response to injury. The proliferation and differentiation of Müller glia-derived progenitors can be controlled by intrinsic and extrinsic factors. We propose a retinal regeneration therapy based on the manipulation of these endogenous progenitors. Here, we review adult neurogenesis and retinal regeneration in mammals, with an emphasis on the neurogenic role of glial cells.

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There is increasing evidence that malignant tumors, such as leukemia, breast cancers, and brain cancers, contain cells that maintain the characteristics of tissue-specific stem cells and are malignant. Malignant glioma, for example, contain both proliferating cells expressing stem cell markers and differentiating cells expressing either neuronal markers or glial markers, raising the possibility that the tumors may contain neural stem cell (NSC)-like cells. This idea is supported by recent findings that malignant glioma can be generated from both NSCs and glial lineage cells, such as oligodendrocyte precursor cells or astrocytes, which behave as NSC-like cells in appropriate conditions. Additional evidence also exists indicating that malignant tumors might contain stem cell-like cancer cells, called &lquo;cancer stem cells&rquo; (CSCs). Although a number of anti-cancer drugs and irradiation have been successful in eliminating cancers, some cancer cells survive and the cancer recurs, indicating that the surviving cells are not only resistant to such anti-cancer drugs and irradiation but are also malignant. Previous studies have shown that various ATP binding cassette transporters, such as the protein encoded by the multi-drug resistant protein and the breast cancer resistant protein 1 (BCRP1), contribute to drug resistance in cancers. Interestingly, some of these transporters are also expressed in many kinds of normal stem cells. BCRP1, for example, excludes the fluorescent dye Hoechst 33342, identifying a side population (SP), which is enriched for stem cells. Together, these findings suggest that cancers might contain an SP that is enriched for cells that have the characteristics of CSCs. Taking advantage of the common characteristics between stem cells and cancer cells, several groups have demonstrated that such stem cell-like cancer cells, although not other cells, in tumors or cancer cell lines can self-renew, express well-known stem cell markers such as CD133, and form tumors when transplanted in vivo, suggesting that tumors contain CSCs and that stem cells might be the primary target of tumorigenesis. In order to develop effective therapy against tumors, characterizing and finding ways to kill CSCs is essential.

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We have generated the first TNFR1-selective antagonistic TNF mutant based on structural human TNF variants using our phage display technology. This TNF mutant did not activate TNFR1-mediated responses, although its affinity for TNFR1 was equivalent to human wild-type TNF (wtTNF). The TNF mutant neutralized wtTNF-induced TNFR1-mediated bioactivity without influencing TNFR2-mediated bioactivity. In hepatitis mouse models, the antagonistic TNF mutant significantly blocked liver injury caused by inflammation. These results indicate that antagonistic TNF mutants may be clinically useful for anti-TNF therapy and that phage display libraries of protein ligands can be used to select for receptor subtype-selective antagonists.

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Purpose: To expect disease-modified anti-rheumatic drugs (DMARDs) combination therapy on rheumatoid arthritis (RA), combination effect of bucillamine (Buc) and methotrexate (MTX) on type II collagen-induced arthritis model (CIA) was investigated. IgM production from B lymphocytes was examined to understand one of the mechanisms of combination effects.
Methods: Rat CIA was induced by bovine type II collagen (CII) sensitization. Buc 3 mg/kg was orally administrated once daily for 21 days from the day of sensitization. MTX 0.2 mg/kg was orally administrated on three times a week for three weeks as the mimic of the clinical dose. IgM production from B lymphocytes was examined with the stimulation of IL-2 and Staphylococcus aureus, and Buc or MTX were treated in vitro.
Results: Buc and MTX combination additively reduced the hind paw swelling and bone destruction in CIA. α1-acidic glycoprotein, one of the inflammation markers in serum, and anti-CII antibody titer were also decreased. Buc and MTX combination additively reduced Staphylococcus aureus and IL-2 induced IgM production from B lymphocytes in vitro.
Conclusion: This study provides the first evidence that Buc exerts additive effect with MTX in CIA rats. Regulating B cell function by Buc and MTX may contribute to their additive effects on rat CIA to some degree.

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The 4th Zoo Meeting was held in Amsterdam, Netherlands, October 4-7, 2006. This meeting is named for the location of the conference, which is adjacent to the zoo. For this meeting, approximately 100 investigators from all over the world gathered to discuss their most recent and exciting data on cell adhesion and migration in inflammation and cancer. Presentations were given as talks or posters. Here we summarize some of the key findings that were discussed at the meeting.

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