Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors.
We examined the effects of retinoids on the human mast cell development using a serum-deprived culture system. When 10-week cultured mast cells derived from CD34(+) cord blood cells were used as target cells, both all-trans retinoic acid (ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF plus RA at 10(-7) mol/L was one tenth of the value obtained by SCF alone). The early steps in mast cell development appear to be less sensitive to RA according to the single CD34(+)c-kit(+) cord blood cell culture study. The optimal concentration of RAs also reduced the histamine concentration in the cultured mast cells (3.00 +/- 0.47 pg per cell in SCF alone, 1.44 +/- 0.18 pg per cell in SCF+ATRA, and 1.41 +/- 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed the expression of RARalpha, RARbeta, RXRalpha, and RXRbeta messenger ribonucleic acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective agonist at 10(-10) mol/L to 10(-7) mol/L decreased the number of mast cells grown in SCF, whereas an RXR-selective agonist at up to 10(-8) mol/L was inactive. Among RAR subtype selective retinoids used at 10(-9) mol/L to 10(-7) mol/L, only the RARalpha agonist was equivalent to ATRA at 10(-7) mol/L in its ability to inhibit mast cell growth. Conversely, the addition of excess concentrations of a RARalpha antagonist profoundly counteracted the retinoid-mediated suppressive effects. These results suggest that RA inhibits SCF-dependent differentiation of human mast cell progenitors through a specific receptor. (Blood. 2000;95:2821-2828)
Kinoshita
T
T
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
Koike
K
K
Mwamtemi
H H
HH
Ito
S
S
Ishida
S
S
Nakazawa
Y
Y
Kurokawa
Y
Y
Sakashita
K
K
Higuchi
T
T
Takeuchi
K
K
Sawai
N
N
Shiohara
M
M
Kamijo
T
T
Kawa
S
S
Yamashita
T
T
Komiyama
A
A
D000077556:Alitretinoin; D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D005312:Fetal Blood / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006632:Histamine / Q000502:physiology; D006801:Humans; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D019089:Stem Cell Factor / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D016895:Culture Media, Serum-Free; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D019089:Stem Cell Factor; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit