title: The beneficial effects of treatment with all-trans-retinoic acid plus corticosteroid on autoimmune nephritis in NZB/WF mice.
abstract: Corticosteroids are highly effective anti-inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All-trans-retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti-inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid-sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti-DNA antibody production were determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P <0.05). A single administration of ATRA reduced the Th1 [interleukin (IL)-2, interferon (IFN)-gamma and IL-12], and a Th2 (IL-4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)-specific anti-DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid-sparing drug against lupus nephritis.
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Kinki University School of Medicine, Osaka, Japan. nozaki@int3.med.kindai.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Nozaki
authors.forename: T
authors.initials: T
authors.lastname: Yamagata
authors.forename: B-S
authors.initials: BS
authors.lastname: Yoo
authors.forename: M
authors.initials: M
authors.lastname: Sugiyama
authors.forename: S
authors.initials: S
authors.lastname: Ikoma
authors.forename: K
authors.initials: K
authors.lastname: Kinoshita
authors.forename: M
authors.initials: M
authors.lastname: Funauchi
authors.forename: A
authors.initials: A
authors.lastname: Kanamaru
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000974:Antibodies, Antinuclear / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004247:DNA / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000032:analysis; D007150:Immunohistochemistry / Q000379:methods; D007641:Keratolytic Agents / Q000627:therapeutic use; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D008814:Mice, Inbred NZB; D019001:Nitric Oxide Synthase / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D011239:Prednisolone / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000187:drug effects; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D000974:Antibodies, Antinuclear; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D005938:Glucocorticoids; D007074:Immunoglobulin G; D007641:Keratolytic Agents; D012333:RNA, Messenger; D014212:Tretinoin; D004247:DNA; D011239:Prednisolone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse