The fungal lactone oxacyclododecindione is a potential new therapeutic substance in the treatment of lupus-associated kidney disease.
Recently oxacyclododecindione (Oxa), a macrocyclic lactone isolated from the imperfect fungus Exserohilum rostratum, has been described as a potent transcription inhibitor of inducible proinflammatory and profibrotic genes in cell culture models. As kidney disease in systemic lupus erythematosus is characterized by aberrant expression of inflammatory mediators and infiltration of immune cells, we investigated the effect of Oxa in MRL-Fas(lpr) mice, a model of systemic lupus erythematosus. These mice develop a spontaneous T-cell and macrophage-dependent autoimmune disease including severe glomerulonephritis that shares features with human lupus. Comparable to the results of in vitro models, we found a reduced expression of the cytokines IFN-γ, IL-6, and TNF-α and the chemokines CCL2, RANTES, and CSF-1 on mRNA and protein level in the kidney of Oxa-treated MRL-Fas(lpr) mice. Accordingly, Oxa treatment reduced the infiltration of immune cells and the frequency of activated proinflammatory T cells in the kidney. Moreover, kidney disease, measured by histopathology, IgG and collagen deposition, and proteinuria, was ameliorated in Oxa-treated MRL-Fas(lpr) mice compared with the control group. Thus, Oxa is a new effective anti-inflammatory compound, which may serve as base structure for the development of new therapeutics for the treatment of chronic inflammatory and/or fibrotic diseases.
Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Jenny
J
Henke
Department of Molecular Biotechnology and Systems Biology, Technical University Kaiserslautern, Kaiserslautern, Germany.
Gerhard
G
Erkel
Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Christoph
C
Brochhausen
Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Hartmut
H
Kleinert
1st Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Andreas
A
Schwarting
1st Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Julia
J
Menke
Department of Pharmacology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Andrea
A
Pautz
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D040501:Calgranulin A / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D053495:Osteopontin / Q000235:genetics; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D040501:Calgranulin A; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D054370:Chemokine CXCL9; D016207:Cytokines; D015850:Interleukin-6; D047028:Macrocyclic Compounds; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C532274:oxacyclododecindione; D053495:Osteopontin; D007371:Interferon-gamma