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Tacrolimus causes a blockage of protein secretion which reinforces its immunosuppressive activity and also explains some of its toxic side-effects.
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- Author(s): Rauch MC;Rauch MC; San Martín A; Ojeda D; Quezada C; Salas M; Cárcamo JG; Yañez AJ; Slebe JC; Claude A
- Source:
Transplant immunology [Transpl Immunol] 2009 Dec; Vol. 22 (1-2), pp. 72-81. Date of Electronic Publication: 2009 Jul 21.- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9309923 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5492 (Electronic) Linking ISSN: 09663274 NLM ISO Abbreviation: Transpl Immunol Subsets: MEDLINE
- Publication Information: Publication: Amsterdam : Elsevier
Original Publication: Dunton Green, Sevenoaks, Kent, UK : Edward Arnold, c1993- - Subject Terms: Immunosuppression Therapy*; Immunosuppressive Agents/*adverse effects ; Immunosuppressive Agents/*pharmacology ; Proteins/*metabolism ; Secretory Pathway/*drug effects ; Tacrolimus/*adverse effects ; Tacrolimus/*pharmacology; Animals ; Brefeldin A/pharmacology ; Cell Line, Tumor ; Gene Expression/drug effects ; Gene Expression/genetics ; Glucose/pharmacology ; Golgi Apparatus/metabolism ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Interleukin-2/genetics ; Interleukin-2/metabolism ; Jurkat Cells ; Lymphocyte Activation/drug effects ; Mice ; Phytohemagglutinins/pharmacology ; Proteins/genetics ; T-Lymphocytes/drug effects ; T-Lymphocytes/metabolism ; Tetradecanoylphorbol Acetate/pharmacology
- Abstract: Background: Tacrolimus (FK506) is a macrolide immunosuppressant drug from the calcineurin inhibitor family, widely used in solid organ and islet cell transplantation, but produces significant side-effects.
Objective: This study examined the effect of FK506 on interleukin-2 (IL-2) and insulin secretion, establishing a novel characteristic of this drug that could explain its diverse adverse effects, and developed an experimental model for the simultaneous analysis of mRNA expression and protein secretion affected by this drug.
Methods: The IL-2 levels when tacrolimus was administered were analysed by Western blot, immunocytochemistry and RT-PCR in a T lymphocyte cellular line (Jurkat) 24 h post-stimulation. The insulin levels when tacrolimus was administered were analysed 4 h after stimulation of glucose-induced insulin secretion in a pancreatic cellular line (MIN6).
Results: The previously published information describes tacrolimus as only capable of partially blocking IL-2 mRNA expression. In our hands, the cellular content of IL-2 is almost undetectable in stimulated Jurkat cells and can be detected in cellular extracts only when the secretory pathway is blocked by brefeldin A (BFA). BFA added 2 h after the beginning of stimulation was able to inhibit IL-2 secretion, without affecting IL-2 mRNA expression. Therefore BFA utilization allowed us to establish a model to analyze the effect on IL-2 secretion, separately from its expression. Tacrolimus added before stimulation inhibits only IL-2 synthesis, but blocks IL-2 protein secretion when added 2 h after stimulation. Similarly, tacrolimus is also capable of blocking the glucose-stimulated secretion of insulin by MIN6 cells. An increase of the intracellular content can be detected concomitantly with a decrease of the hormone measured in the culture medium.
Conclusions: Results of this study indicate that tacrolimus possesses another important effect in addition to the inhibition of IL-2 gene transcription, namely the ability to act as a general inhibitor of the protein secretory pathway. These results strongly suggest that the diabetogenic effect of the immune suppressant FK506 could be caused by the blockade of insulin secretion. This novel effect also provides an explanation for other side-effects observed in immunosuppressive treatment. - Accession Number: 0 (GBF1 protein, human)
0 (Guanine Nucleotide Exchange Factors)
0 (Immunosuppressive Agents)
0 (Insulin)
0 (Interleukin-2)
0 (Phytohemagglutinins)
0 (Proteins)
20350-15-6 (Brefeldin A)
IY9XDZ35W2 (Glucose)
NI40JAQ945 (Tetradecanoylphorbol Acetate)
WM0HAQ4WNM (Tacrolimus) - Publication Date: Date Created: 20090725 Date Completed: 20100204 Latest Revision: 20211203
- Publication Date: 20240104
- Accession Number: 10.1016/j.trim.2009.07.001
- Accession Number: 19628039
- Source:
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