title: Sirolimus interferes with the innate response to bacterial products in human whole blood by attenuation of IL-10 production.
abstract: 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)-alpha 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.
authors.affiliation: Institute for Surgical Research, The National Hospital, N-0027 Oslo, Norway. p.f.jorgensen@klinmed.uio.no
authors.forename: P F
authors.initials: PF
authors.lastname: Jørgensen
authors.forename: J E
authors.initials: JE
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Almlöf
authors.forename: R
authors.initials: R
authors.lastname: Solberg
authors.forename: C
authors.initials: C
authors.lastname: Okkenhaug
authors.forename: T
authors.initials: T
authors.lastname: Scholz
authors.forename: C
authors.initials: C
authors.lastname: Thiemermann
authors.forename: S J
authors.initials: SJ
authors.lastname: Foster
authors.forename: A O
authors.initials: AO
authors.lastname: Aasen
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000494:pharmacology; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology; D013682:Teichoic Acids / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C009900:lipoteichoic acid; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus