Effects of cyclosporin A and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA in mouse bone marrow-derived progenitor mast cells: resistance to FK506 is associated with a deficiency in FK506-binding protein FKBP12.
The inhibitory effects of cyclosporin A (CsA) and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA and the expression of their intracellular binding proteins were studied in interleukin 3 (IL-3)-dependent, mouse bone marrow-derived mast cells (BMMCs). In BMMCs sensitized with IgE anti-trinitrophenyl, CsA inhibited trinitrophenylated bovine serum albumin-induced increases in mRNA for IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 in a dose-related manner (IC50 values of 4, 65, and 130 nM, respectively). FK506 did not inhibit hapten-specific increases of mRNA for TNF-alpha or IL-6, and for IL-1 beta the IC50 was greater than 50-fold higher than that of CsA. Neither agent inhibited exocytosis of the endogenous secretory granule mediators beta-hexosaminidase and histamine at the IC50 values for inhibition of increases in cytokine mRNA. BMMCs expressed cyclophilin, and CsA inhibited the phosphatase activity of cellular calcineurin with an IC50 of approximately 8 nM. That CsA inhibited IL-1 beta mRNA accumulation in IgE-activated BMMCs with an IC50 similar to that for inhibition of calcineurin activity, whereas the IC50 values were approximately 20-fold higher for the inhibition of TNF-alpha and IL-6 mRNA, suggests that the induction of TNF-alpha and IL-6 is less dependent upon calcineurin activity than is the induction of IL-1 beta. BMMCs were deficient in the 12-kDa FK506-binding protein FKBP12, but not FKBP13, as assessed by RNA and protein blot analyses. FK506 did not inhibit calcineurin phosphatase activity in BMMCs, even at drug concentrations of 1000 nM. The resistance of BMMCs to inhibition of Fc epsilon receptor type I-mediated increases in cytokine mRNA by FK506 is most likely due to their deficiency of FKBP12 and the related inability to inhibit the activity of calcineurin.
Kaye
R E
RE
Department of Medicine, Harvard Medical School, Boston, MA 02115.
Fruman
D A
DA
Bierer
B E
BE
Albers
M W
MW
Zydowsky
L D
LD
Ho
S I
SI
Jin
Y J
YJ
Castells
M C
MC
Schreiber
S L
SL
Walsh
C T
CT
D000591:Amino Acid Isomerases / Q000378:metabolism; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001854:Bone Marrow Cells; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D005089:Exocytosis / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011961:Receptors, Fc / Q000502:physiology*; D017455:Receptors, IgE; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D012333:RNA, Messenger; D011961:Receptors, Fc; D017455:Receptors, IgE; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D001619:beta-N-Acetylhexosaminidases; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus