The immunosuppressive and toxic effects of FK-506 are mechanistically related

Pharmacology of a novel antagonist of FK-506 and rapamycin

Francis J. Dumont, Mary Jo Staruch, Samuel L. Koprak, John Siekierka, C. Shirley Lin, Richard Harrison, Tonya Sewell, Victoria M. Kindt, Thomas R. Beattie, Matthew Wyvratt, Nolan H. Sigal

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Abstract

FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with rehted biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis.trans peptidyl-prolyl isomerase activity (PPlase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufcient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used b685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although b685,818 bound with high afnity to FKBP-12 and inhibited its PPlase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, b685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPlase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

Original languageEnglish
Pages (from-to)751-760
Number of pages10
JournalJournal of Experimental Medicine
Volume176
Issue number3
DOIs
StatePublished - 1 Sep 1992

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Poisons
Tacrolimus
Sirolimus
Immunosuppressive Agents
Carrier Proteins
Pharmacology
T-Lymphocytes
Lymphokines
L 685818
Immunosuppression
Biochemical Phenomena
Peptidylprolyl Isomerase
Toxic Actions
Dogs

Cite this

Dumont, Francis J. ; Staruch, Mary Jo ; Koprak, Samuel L. ; Siekierka, John ; Lin, C. Shirley ; Harrison, Richard ; Sewell, Tonya ; Kindt, Victoria M. ; Beattie, Thomas R. ; Wyvratt, Matthew ; Sigal, Nolan H. / The immunosuppressive and toxic effects of FK-506 are mechanistically related : Pharmacology of a novel antagonist of FK-506 and rapamycin. In: Journal of Experimental Medicine. 1992 ; Vol. 176, No. 3. pp. 751-760.
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title = "The immunosuppressive and toxic effects of FK-506 are mechanistically related: Pharmacology of a novel antagonist of FK-506 and rapamycin",
abstract = "FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with rehted biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis.trans peptidyl-prolyl isomerase activity (PPlase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufcient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used b685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although b685,818 bound with high afnity to FKBP-12 and inhibited its PPlase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, b685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPlase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.",
author = "Dumont, {Francis J.} and Staruch, {Mary Jo} and Koprak, {Samuel L.} and John Siekierka and Lin, {C. Shirley} and Richard Harrison and Tonya Sewell and Kindt, {Victoria M.} and Beattie, {Thomas R.} and Matthew Wyvratt and Sigal, {Nolan H.}",
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Dumont, FJ, Staruch, MJ, Koprak, SL, Siekierka, J, Lin, CS, Harrison, R, Sewell, T, Kindt, VM, Beattie, TR, Wyvratt, M & Sigal, NH 1992, 'The immunosuppressive and toxic effects of FK-506 are mechanistically related: Pharmacology of a novel antagonist of FK-506 and rapamycin', Journal of Experimental Medicine, vol. 176, no. 3, pp. 751-760. https://doi.org/10.1084/jem.176.3.751

The immunosuppressive and toxic effects of FK-506 are mechanistically related : Pharmacology of a novel antagonist of FK-506 and rapamycin. / Dumont, Francis J.; Staruch, Mary Jo; Koprak, Samuel L.; Siekierka, John; Lin, C. Shirley; Harrison, Richard; Sewell, Tonya; Kindt, Victoria M.; Beattie, Thomas R.; Wyvratt, Matthew; Sigal, Nolan H.

In: Journal of Experimental Medicine, Vol. 176, No. 3, 01.09.1992, p. 751-760.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The immunosuppressive and toxic effects of FK-506 are mechanistically related

T2 - Pharmacology of a novel antagonist of FK-506 and rapamycin

AU - Dumont, Francis J.

AU - Staruch, Mary Jo

AU - Koprak, Samuel L.

AU - Siekierka, John

AU - Lin, C. Shirley

AU - Harrison, Richard

AU - Sewell, Tonya

AU - Kindt, Victoria M.

AU - Beattie, Thomas R.

AU - Wyvratt, Matthew

AU - Sigal, Nolan H.

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N2 - FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with rehted biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis.trans peptidyl-prolyl isomerase activity (PPlase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufcient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used b685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although b685,818 bound with high afnity to FKBP-12 and inhibited its PPlase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, b685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPlase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

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