Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients.
OBJECTIVE
Immune status is altered during systemic inflammatory response syndrome and sepsis. Reduced ex vivo tumor necrosis factor production has been regularly reported with lipopolysaccharide-activated monocytes. In this study, we addressed the specificity of this hyporeactivity and investigated some of the possible associated mechanistic events.


METHODS
Ex vivo study.


METHODS
Academic research laboratory.


METHODS
Healthy controls, septic patients, and resuscitated patients after cardiac arrest (RCA). This latter group presents a systemic inflammatory response syndrome of noninfectious origin.


METHODS
None.


RESULTS
We investigated the reactivity of patients' monocytes in terms of cytokine production, after stimulation with a Toll-like receptor (TLR) 2 (Pam3CysSK4), a TLR4 (lipopolysaccharide), a Nod2 agonist (muramyl dipeptide), or heat-killed bacteria. We also investigated the contribution of phagocytosis in cytokine production, studied the expression of intracellular bacterial peptidoglycan sensors (Nod1 and Nod2), and analyzed the messenger RNA expression of inhibitors of TLR signaling: Toll interacting protein (Tollip), suppressor of cytokine signaling-1 (SOCS1), myeloid differentiation 88 short (MyD88s), and single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR). In sepsis, tumor necrosis factor production in response to lipopolysaccharide and Pam3CysSK4 was reduced, whereas interleukin-10 production was enhanced. The responsiveness to Staphylococcus aureus, Escherichia coli, and muramyl dipeptide and the expression of Nod1 and Nod2 were similar to those obtained for healthy donors. The messenger RNA expression of Tollip and SOCS1 was unchanged, whereas that of MyD88s and SIGIRR was significantly enhanced compared with healthy controls. Monocytes from RCA patients showed a reduced production of tumor necrosis factor in response to lipopolysaccharide but neither to Pam3CysSK4 nor to heat-killed bacteria. They displayed an increased expression of SIGIRR but not of MyD88s. We showed that TLR2-dependent nuclear factor-kappaB activation was inhibited by MyD88s but not by SIGIRR. This result may explain the normal tumor necrosis factor production through TLR2 observed for monocytes of RCA patients.


CONCLUSIONS
There is a "reprogramming" of monocyte reactivity, and not a global hyporeactivity, during systemic inflammation, which differs in septic and RCA patients.
Adib-Conquy
Minou
M
Cytokines & Inflammation Unit, Institut Pasteur, Paris, France. madib@pasteur.fr
Adrie
Christophe
C
Fitting
Catherine
C
Gattolliat
Olivier
O
Beyaert
Rudi
R
Cavaillon
Jean-Marc
JM
D000119:Acetylmuramyl-Alanyl-Isoglutamine; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002478:Cells, Cultured; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D006323:Heart Arrest / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine