Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Sep 15;89(18):8542–8546. doi: 10.1073/pnas.89.18.8542

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.

R E Kaye 1, D A Fruman 1, B E Bierer 1, M W Albers 1, L D Zydowsky 1, S I Ho 1, Y J Jin 1, M C Castells 1, S L Schreiber 1, C T Walsh 1, et al.
PMCID: PMC49956  PMID: 1382293

Abstract

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.

Full text

PDF
8542

Images in this article

8544Image
on p.8544
8544Image
on p.8544
8545Image
on p.8545

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  2. Bialojan C., Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem J. 1988 Nov 15;256(1):283–290. doi: 10.1042/bj2560283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burd P. R., Rogers H. W., Gordon J. R., Martin C. A., Jayaraman S., Wilson S. D., Dvorak A. M., Galli S. J., Dorf M. E. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med. 1989 Jul 1;170(1):245–257. doi: 10.1084/jem.170.1.245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Forrest M. J., Jewell M. E., Koo G. C., Sigal N. H. FK-506 and cyclosporin A: selective inhibition of calcium ionophore-induced polymorphonuclear leukocyte degranulation. Biochem Pharmacol. 1991 Aug 22;42(6):1221–1228. doi: 10.1016/0006-2952(91)90257-6. [DOI] [PubMed] [Google Scholar]
  6. Friedman J., Weissman I. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell. 1991 Aug 23;66(4):799–806. doi: 10.1016/0092-8674(91)90123-g. [DOI] [PubMed] [Google Scholar]
  7. Fruman D. A., Klee C. B., Bierer B. E., Burakoff S. J. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3686–3690. doi: 10.1073/pnas.89.9.3686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gray P. W., Glaister D., Chen E., Goeddel D. V., Pennica D. Two interleukin 1 genes in the mouse: cloning and expression of the cDNA for murine interleukin 1 beta. J Immunol. 1986 Dec 1;137(11):3644–3648. [PubMed] [Google Scholar]
  9. Hultsch T., Albers M. W., Schreiber S. L., Hohman R. J. Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6229–6233. doi: 10.1073/pnas.88.14.6229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hultsch T., Rodriguez J. L., Kaliner M. A., Hohman R. J. Cyclosporin A inhibits degranulation of rat basophilic leukemia cells and human basophils. Inhibition of mediator release without affecting PI hydrolysis or Ca2+ fluxes. J Immunol. 1990 Apr 1;144(7):2659–2664. [PubMed] [Google Scholar]
  11. Jin Y. J., Albers M. W., Lane W. S., Bierer B. E., Schreiber S. L., Burakoff S. J. Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6677–6681. doi: 10.1073/pnas.88.15.6677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Katz H. R., Kaye R. E., Austen K. F. Mast cell biochemical and functional heterogeneity. Transplant Proc. 1991 Dec;23(6):2900–2904. [PubMed] [Google Scholar]
  13. Kharazmi A., Svenson M., Nielsen H., Birgens H. S. Effect of cyclosporin A on human neutrophil and monocyte function. Scand J Immunol. 1985 Jun;21(6):585–591. doi: 10.1111/j.1365-3083.1985.tb01848.x. [DOI] [PubMed] [Google Scholar]
  14. Lancki D. W., Kaper B. P., Fitch F. W. The requirements for triggering of lysis by cytolytic T lymphocyte clones. II. Cyclosporin A inhibits TCR-mediated exocytosis by only selectively inhibits TCR-mediated lytic activity by cloned CTL. J Immunol. 1989 Jan 15;142(2):416–424. [PubMed] [Google Scholar]
  15. Liu J., Farmer J. D., Jr, Lane W. S., Friedman J., Weissman I., Schreiber S. L. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815. doi: 10.1016/0092-8674(91)90124-h. [DOI] [PubMed] [Google Scholar]
  16. Nakano T., Sonoda T., Hayashi C., Yamatodani A., Kanayama Y., Yamamura T., Asai H., Yonezawa T., Kitamura Y., Galli S. J. Fate of bone marrow-derived cultured mast cells after intracutaneous, intraperitoneal, and intravenous transfer into genetically mast cell-deficient W/Wv mice. Evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells. J Exp Med. 1985 Sep 1;162(3):1025–1043. doi: 10.1084/jem.162.3.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Otsu K., Nakano T., Kanakura Y., Asai H., Katz H. R., Austen K. F., Stevens R. L., Galli S. J., Kitamura Y. Phenotypic changes of bone marrow-derived mast cells after intraperitoneal transfer into W/Wv mice that are genetically deficient in mast cells. J Exp Med. 1987 Mar 1;165(3):615–627. doi: 10.1084/jem.165.3.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pedersen C., Permin H., Stahl Skov P., Norn S., Svenson M., Mosbech H., Bendtzen K. Inhibitory effect of cyclosporin A on histamine release from human leukocytes and rat mast cells. Allergy. 1985 Feb;40(2):103–107. doi: 10.1111/j.1398-9995.1985.tb02668.x. [DOI] [PubMed] [Google Scholar]
  19. Price E. R., Zydowsky L. D., Jin M. J., Baker C. H., McKeon F. D., Walsh C. T. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1903–1907. doi: 10.1073/pnas.88.5.1903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Razin E., Ihle J. N., Seldin D., Mencia-Huerta J. M., Katz H. R., LeBlanc P. A., Hein A., Caulfield J. P., Austen K. F., Stevens R. L. Interleukin 3: A differentiation and growth factor for the mouse mast cell that contains chondroitin sulfate E proteoglycan. J Immunol. 1984 Mar;132(3):1479–1486. [PubMed] [Google Scholar]
  21. Razin E., Mencia-Huerta J. M., Stevens R. L., Lewis R. A., Liu F. T., Corey E., Austen K. F. IgE-mediated release of leukotriene C4, chondroitin sulfate E proteoglycan, beta-hexosaminidase, and histamine from cultured bone marrow-derived mouse mast cells. J Exp Med. 1983 Jan 1;157(1):189–201. doi: 10.1084/jem.157.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Robinson D., Stirling J. L. N-Acetyl-beta-glucosaminidases in human spleen. Biochem J. 1968 Apr;107(3):321–327. doi: 10.1042/bj1070321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rudolph A. K., Burrows P. D., Wabl M. R. Thirteen hybridomas secreting hapten-specific immunoglobulin E from mice with Iga or Igb heavy chain haplotype. Eur J Immunol. 1981 Jun;11(6):527–529. doi: 10.1002/eji.1830110617. [DOI] [PubMed] [Google Scholar]
  24. Sawada S., Suzuki G., Kawase Y., Takaku F. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol. 1987 Sep 15;139(6):1797–1803. [PubMed] [Google Scholar]
  25. Schreiber S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991 Jan 18;251(4991):283–287. doi: 10.1126/science.1702904. [DOI] [PubMed] [Google Scholar]
  26. Seldin D. C., Adelman S., Austen K. F., Stevens R. L., Hein A., Caulfield J. P., Woodbury R. G. Homology of the rat basophilic leukemia cell and the rat mucosal mast cell. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3871–3875. doi: 10.1073/pnas.82.11.3871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Seldin D. C., Austen K. F., Stevens R. L. Purification and characterization of protease-resistant secretory granule proteoglycans containing chondroitin sulfate di-B and heparin-like glycosaminoglycans from rat basophilic leukemia cells. J Biol Chem. 1985 Sep 15;260(20):11131–11139. [PubMed] [Google Scholar]
  28. Spiegelman B. M., Frank M., Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem. 1983 Aug 25;258(16):10083–10089. [PubMed] [Google Scholar]
  29. Standaert R. F., Galat A., Verdine G. L., Schreiber S. L. Molecular cloning and overexpression of the human FK506-binding protein FKBP. Nature. 1990 Aug 16;346(6285):671–674. doi: 10.1038/346671a0. [DOI] [PubMed] [Google Scholar]
  30. Stevens R. L., Lee T. D., Seldin D. C., Austen K. F., Befus A. D., Bienenstock J. Intestinal mucosal mast cells from rats infected with Nippostrongylus brasiliensis contain protease-resistant chondroitin sulfate di-B proteoglycans. J Immunol. 1986 Jul 1;137(1):291–295. [PubMed] [Google Scholar]
  31. Swanson S. K., Born T., Zydowsky L. D., Cho H., Chang H. Y., Walsh C. T., Rusnak F. Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3741–3745. doi: 10.1073/pnas.89.9.3741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Theoharides T. C., Bondy P. K., Tsakalos N. D., Askenase P. W. Differential release of serotonin and histamine from mast cells. Nature. 1982 May 20;297(5863):229–231. doi: 10.1038/297229a0. [DOI] [PubMed] [Google Scholar]
  33. Theoharides T. C., Kops S. K., Bondy P. K., Askenase P. W. Differential release of serotonin without comparable histamine under diverse conditions in the rat mast cell. Biochem Pharmacol. 1985 May 1;34(9):1389–1398. doi: 10.1016/0006-2952(85)90675-6. [DOI] [PubMed] [Google Scholar]
  34. Tocci M. J., Matkovich D. A., Collier K. A., Kwok P., Dumont F., Lin S., Degudicibus S., Siekierka J. J., Chin J., Hutchinson N. I. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989 Jul 15;143(2):718–726. [PubMed] [Google Scholar]
  35. Todo S., Ueda Y., Demetris J. A., Imventarza O., Nalesnik M., Venkataramanan R., Makowka L., Starzl T. E. Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction. Surgery. 1988 Aug;104(2):239–249. [PMC free article] [PubMed] [Google Scholar]
  36. Van Snick J., Cayphas S., Szikora J. P., Renauld J. C., Van Roost E., Boon T., Simpson R. J. cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol. 1988 Feb;18(2):193–197. doi: 10.1002/eji.1830180202. [DOI] [PubMed] [Google Scholar]
  37. de Paulis A., Cirillo R., Ciccarelli A., Condorelli M., Marone G. FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells. J Immunol. 1991 Apr 1;146(7):2374–2381. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES