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Sirolimus Interferes with the Innate Response to Bacterial Products in Human Whole Blood by Attenuation of IL‐10 Production
Author(s) -
Jørgensen P. F.,
Wang J. E.,
Almlöf M.,
Solberg R.,
Okkenhaug C.,
Scholz T.,
Thiemermann C.,
Foster S. J.,
Aasen A. O.
Publication year - 2001
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.2001.00862.x
Subject(s) - lipoteichoic acid , sirolimus , innate immune system , lipopolysaccharide , peripheral blood mononuclear cell , immune system , immunology , cytokine , tumor necrosis factor alpha , whole blood , biology , peptidoglycan , sepsis , in vitro , bacteria , staphylococcus aureus , biochemistry , genetics
Current immunosuppressive strategies are aimed at abrogating the allospecific T‐cell response against donor tissues or organs. However, little information is yet available on the potential influences of these drugs on innate immune responses. In order to address this, we have employed a whole blood model. Human whole blood was pretreated with sirolimus, cyclosporine A or tacrolimus in therapeutic as well as supra therapeutic doses, and subsequently stimulated with lipopolysaccharide (LPS), peptidoglycan (PepG) or lipoteichoic acid (LTA). Plasma cytokine analyses revealed a potent inhibitory effect of sirolimus on interleukin(IL)‐10 production induced by all bacterial products tested. In contrast, cyclosporine A and tacrolimus inhibited the tumour necrosis factor (TNF)‐α production in response to LPS, but not to PepG and LTA. Using a quantitative mRNA analyses, we also observed that sirolimus significantly decreased the IL‐10 mRNA accumulation to sub‐basal levels in peripheral blood mononuclear cells (PBMC). This suggests that the sirolimus inhibits IL‐10 production by interfering with the IL‐10 gene transcription. However, the molecular mechanism of this inhibition remains unclear. Based on the present study and observations by others, we postulate that the clinical use of the sirolimus may be associated with a dysregulated innate immune response to bacterial infection and thus an increased risk of hyperinflammation and sepsis.