Circulating neutrophils of septic patients constitutively express IL-10R1 and are promptly responsive to IL-10.
Previous studies have demonstrated that neutrophils isolated from the blood of healthy donors do not respond to IL-10 in terms of either activation of signal transducer and activator of transcription-3 (STAT3) tyrosine phosphorylation or induction of suppressor of cytokine signalling (SOCS)-3 protein, unlike autologous mononuclear cells. This was explained by the fact that circulating neutrophils of healthy donors express only IL-10R2, but not IL-10R1, the latter IL-10R chain being essential for mediating IL-10 responsiveness. In this study, we report that peripheral blood neutrophils of septic patients constitutively display, besides IL-10R2, also abundant levels of surface IL-10R1. Consequently, septic neutrophils are promptly responsive to IL-10 in vitro, as revealed by a direct IL-10-mediated induction of STAT3 tyrosine phosphorylation and SOCS-3 gene transcription, mRNA and protein expression. Consistent with the presence of a fully functional IL-10R, modulation of LPS-induced CXCL8, CCL4, tumour necrosis factor-alpha and IL-1ra gene expression was also rapidly induced by IL-10 in septic, but not normal, neutrophils. Collectively, these data uncover that neutrophils of septic patients are predisposed to be promptly responsive to IL-10, presumably to help limiting their pro-inflammatory state. They also fully validate our previous observations, herein in the context of a human disease, that responsiveness of human neutrophils to IL-10 is strictly dependent upon the modulation of IL-10R1 expression.
Tamassia
Nicola
N
Department of Pathology, Division of General Pathology, University of Verona, Verona, Italy.
Calzetti
Federica
F
Menestrina
Nicola
N
Rossato
Marzia
M
Bazzoni
Flavia
F
Gottin
Leonardo
L
Cassatella
Marco A
MA
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D053709:Interleukin-10 Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D053709:Interleukin-10 Receptor alpha Subunit; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10