Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production.
Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.
Xiao
Zhi-Yong
ZY
Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Haidian District, Beijing 100850, PR China.
Zhou
Wen-Xia
WX
Zhang
Yong-Xiang
YX
Cheng
Jun-Ping
JP
He
Jun-Feng
JF
Yang
Ri-Fang
RF
Yun
Liu-Hong
LH
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D006912:Hydroxyquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011507:Proteinuria / Q000517:prevention & control; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D016207:Cytokines; D006912:Hydroxyquinolines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D014280:Triglycerides; C045282:roquinimex; D002784:Cholesterol; D003404:Creatinine