Expression Of SIGIRR Research Articles

Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients*

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. Ex vivo study. Academic research laboratory. Healthy controls, septic patients, and resuscitated patients after cardiac arrest (RCA). This latter group presents a systemic inflammatory response syndrome of noninfectious origin. None. 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. There is a "reprogramming" of monocyte reactivity, and not a global hyporeactivity, during systemic inflammation, which differs in septic and RCA patients.

Gene expression clusters of a lipopolysaccharide‐stimulated pathway in peripheral blood monocytes of Japanese patients with Crohn's disease

SummaryBackgroundRecent reports support the notion that patients with Crohn's disease have a dysregulated innate immune response to endogenous flora.AimTo reveal the distinct gene expression clusters of a lipopolysaccharide‐stimulated pathway in the peripheral blood monocytes of Japanese patients with Crohn's disease.Materials and methodsTotal RNA was extracted from peripheral blood monocytes of four patients in the remission stage of Crohn's disease as well as four controls, and gene expression profiles before and after lipopolysaccharide stimulation were investigated using a high‐density oligonucleotide probe array. To focus on innate immunity, the expression of genes to be studied was narrowed down to 118 probe sets which were selected using the following keywords: lipopolysaccharide, toll, myd and tir along with a software of NetAffx Analysis Center.ResultsUsing hierarchical clustering analysis, we picked up to 44 and 36 probe sets for which expression had decreased before and after lipopolysaccharide stimulation, respectively, in patients with Crohn's disease compared with healthy volunteers. The expression of TLR5, 7, MyD88, SIGIRR, and Tollip was decreased both before and after lipopolysaccharide stimulation in patients with Crohn's disease.ConclusionWe found several interesting clusters in monocytes before and after stimulation with lipopolysaccharide. These genes may have been responsible for the immunological differences between the Crohn's disease and control patients.