All-trans-retinoic acid suppresses interferon-gamma and tumor necrosis factor-alpha; a possible therapeutic agent for rheumatoid arthritis.
OBJECTIVE
To study the effects of all-trans-retinoic acid (ATRA), we determined the proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells in healthy volunteers and patients with rheumatoid arthritis (RA), and explored the possibility of using ATRA as a therapeutic agent for autoimmune diseases.


METHODS
Proliferation of these cells was determined by modified MTT assay, and expression of CC chemokine receptors 4 (CCR4) and CCR5 was determined by flow cytometry. Production and expression of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and tumor necrosis factor (TNF)-alpha was determined by Enzyme-Linked Immunosorbent Assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The presence of STAT6 protein was determined by Western blot analysis.


RESULTS
ATRA did not affect the proliferation or production of IL-2 and IL-4. We did not detect STAT6 protein, and saw no evidence of the differentiation of PBMCs to Th1 or Th2 cells. In contrast, ATRA suppressed the production of IFN-gamma and TNF-alpha significantly. There were no significant differences between the healthy volunteers and RA patients.


CONCLUSIONS
ATRA was demonstrated to affect the cytokine production of IFN-gamma and TNF-alpha. ATRA might be useful in the treatment of autoimmune diseases such as RA.
Nozaki
Yuji
Y
Department of Nephrology and Rheumatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511 Osaka, Japan.
Tamaki
Chise
C
Yamagata
Toshiaki
T
Sugiyama
Masafumi
M
Ikoma
Shinya
S
Kinoshita
Koji
K
Funauchi
Masanori
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects / Q000378:metabolism; D012016:Reference Values; D050800:STAT6 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D018501:Antirheumatic Agents; C515354:CCR4 protein, human; D016207:Cytokines; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D007371:Interferon-gamma