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Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation.
Liver Transpl 2013; 19(10):1099-107LT

Abstract

Toll-like receptors (TLRs) play a key role in transplantation biology. The effect of immunosuppression on TLR function after liver transplantation is unknown. Peripheral blood mononuclear cells (PBMCs) from 113 post-liver transplant patients and 13 healthy controls were stimulated with TLR-specific ligands [lipopolysaccharide (TLR4), pan-3-cys (P3C) (TLR2), Poly (I:C) (PIC) (TLR3), R848 (TLR7/8), and CpG (TLR9)] for 24 hours. PBMCs from 5 healthy controls were also cultured with therapeutic concentrations of cyclosporine A (CYA) and tacrolimus (TAC). Cytokine production was measured with enzyme-linked immunosorbent assays and flow cytometry. PBMCs from patients on calcineurin inhibitors after liver transplantation produced less interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in response to TLR2 stimulation (IL-6: P=0.02; TNFα: P=0.01), TLR4 stimulation (IL-6: P=0.02; TNFα: P=0.01), and TLR7/8 stimulation (IL-6: P=0.02; TNFα: P=0.02), compared with healthy controls. Both CD56(bright) and CD56(dim) natural killer (NK) cells from patients on calcineurin inhibitors also produced less interferon-γ (IFNγ) with TLR7/8 stimulation compared with healthy controls (CD56(bright) : P=0.002; CD56(dim) : P=0.004). Similar findings were demonstrated in healthy PBMCs cultured with CYA (PBMCs: TLR2, IL-6: P=0.005; TLR4, IL-6: P=0.03, TNFα: P=0.03; TLR7/8, IL-6: P=0.02, TNFα: P=0.01; CD56(dim) NK cells: TLR7/8, IFNγ: P=0.03). TAC impaired TLR4-mediated IL-6 and TNFα production by PBMCs (IL-6; P = 0.02; TNFα P = 0.009). In conclusion, patients on calcineurin inhibitors had impaired inflammatory cytokine production in response to TLR2, TLR4, and TLR7/8 stimulation compared comparison with healthy controls. Importantly, TAC and CYA appear to have different effects on TLR signaling. Impaired TLR function has important repercussions for risk of infection, graft rejection, and disease recurrence after transplantation, and the different immunosuppressive profiles of CYA and TAC may guide the choice of therapy to improve disease outcomes.

Authors+Show Affiliations

Liver Transplant Unit, Austin Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23894100

Citation

Howell, Jessica, et al. "Cyclosporine and Tacrolimus Have Inhibitory Effects On Toll-like Receptor Signaling After Liver Transplantation." Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, vol. 19, no. 10, 2013, pp. 1099-107.
Howell J, Sawhney R, Testro A, et al. Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation. Liver Transpl. 2013;19(10):1099-107.
Howell, J., Sawhney, R., Testro, A., Skinner, N., Gow, P., Angus, P., ... Visvanathan, K. (2013). Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation. Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 19(10), pp. 1099-107. doi:10.1002/lt.23712.
Howell J, et al. Cyclosporine and Tacrolimus Have Inhibitory Effects On Toll-like Receptor Signaling After Liver Transplantation. Liver Transpl. 2013;19(10):1099-107. PubMed PMID: 23894100.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclosporine and tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation. AU - Howell,Jessica, AU - Sawhney,Rohit, AU - Testro,Adam, AU - Skinner,Narelle, AU - Gow,Paul, AU - Angus,Peter, AU - Ratnam,Dilip, AU - Visvanathan,Kumar, PY - 2013/02/18/received PY - 2013/06/06/accepted PY - 2013/7/30/entrez PY - 2013/7/31/pubmed PY - 2014/5/6/medline SP - 1099 EP - 107 JF - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society JO - Liver Transpl. VL - 19 IS - 10 N2 - Toll-like receptors (TLRs) play a key role in transplantation biology. The effect of immunosuppression on TLR function after liver transplantation is unknown. Peripheral blood mononuclear cells (PBMCs) from 113 post-liver transplant patients and 13 healthy controls were stimulated with TLR-specific ligands [lipopolysaccharide (TLR4), pan-3-cys (P3C) (TLR2), Poly (I:C) (PIC) (TLR3), R848 (TLR7/8), and CpG (TLR9)] for 24 hours. PBMCs from 5 healthy controls were also cultured with therapeutic concentrations of cyclosporine A (CYA) and tacrolimus (TAC). Cytokine production was measured with enzyme-linked immunosorbent assays and flow cytometry. PBMCs from patients on calcineurin inhibitors after liver transplantation produced less interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in response to TLR2 stimulation (IL-6: P=0.02; TNFα: P=0.01), TLR4 stimulation (IL-6: P=0.02; TNFα: P=0.01), and TLR7/8 stimulation (IL-6: P=0.02; TNFα: P=0.02), compared with healthy controls. Both CD56(bright) and CD56(dim) natural killer (NK) cells from patients on calcineurin inhibitors also produced less interferon-γ (IFNγ) with TLR7/8 stimulation compared with healthy controls (CD56(bright) : P=0.002; CD56(dim) : P=0.004). Similar findings were demonstrated in healthy PBMCs cultured with CYA (PBMCs: TLR2, IL-6: P=0.005; TLR4, IL-6: P=0.03, TNFα: P=0.03; TLR7/8, IL-6: P=0.02, TNFα: P=0.01; CD56(dim) NK cells: TLR7/8, IFNγ: P=0.03). TAC impaired TLR4-mediated IL-6 and TNFα production by PBMCs (IL-6; P = 0.02; TNFα P = 0.009). In conclusion, patients on calcineurin inhibitors had impaired inflammatory cytokine production in response to TLR2, TLR4, and TLR7/8 stimulation compared comparison with healthy controls. Importantly, TAC and CYA appear to have different effects on TLR signaling. Impaired TLR function has important repercussions for risk of infection, graft rejection, and disease recurrence after transplantation, and the different immunosuppressive profiles of CYA and TAC may guide the choice of therapy to improve disease outcomes. SN - 1527-6473 UR - https://www.unboundmedicine.com/medline/citation/23894100/Cyclosporine_and_tacrolimus_have_inhibitory_effects_on_toll_like_receptor_signaling_after_liver_transplantation_ L2 - https://doi.org/10.1002/lt.23712 DB - PRIME DP - Unbound Medicine ER -