Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.
 ...
PMID:CL097, a TLR7/8 ligand, inhibits TLR-4--dependent activation of IRAK-M and BCL-3 expression. 1933 35

Sepsis is the most common cause of acute lung injury (ALI), leading to organ dysfunction and death in critically ill patients. Previous studies associated variants of interleukin-1 receptor-associated kinase genes (IRAKs) with differential immune responses to pathogens and with outcomes during sepsis, and revealed that increased expression levels of the IRAK3 gene were correlated with poor outcomes during sepsis. Here we explored whether common variants of the IRAK3 gene were associated with susceptibility to, and outcomes of, severe sepsis. After our discovery of polymorphism, we genotyped a subset of seven single-nucleotide polymorphisms (SNPs) in 336 population-based control subjects and 214 patients with severe sepsis, collected as part of a prospective study of adults from a Spanish network of intensive care units. Whereas IRAK3 SNPs were not associated with susceptibility to severe sepsis, rs10506481 showed a significant association with the development of ALI among patients with sepsis (P = 0.007). The association remained significant after adjusting for multiple comparisons, population stratification, and clinical variables (odds ratio, 2.50; 95% confidence interval, 1.15-5.47; P = 0.021). By imputation, we revealed three additional SNPs independently associated with ALI (P < 0.01). One of these (rs1732887) predicted the disruption of a putative human-mouse conserved transcription factor binding site, and demonstrated functional effects in vitro (P = 0.017). Despite the need for replication in independent studies, our data suggest that common SNPs in the IRAK3 gene may be determinants of sepsis-induced ALI.
 ...
PMID:Interleukin-1 receptor-associated kinase 3 gene associates with susceptibility to acute lung injury. 2129 81

Antigen presenting cells (APCs) of the innate immune system sense a wide range of pathogens via pattern recognition receptors (PRRs). Engagement of certain PRRs can induce production of pro-inflammatory mediators that facilitate effective clearance of pathogen. Toll-like receptors (TLRs) are a well described group of PRRs that belong to the TLR/Interleukin-1 receptor (IL-1R) superfamily. However, TLR/IL-1R induction of pro-inflammatory mediators must be regulated to prevent excessive inflammation and tissue damage. One molecule of recent interest that is known to inhibit TLR/IL-1R signaling is interleukin-1 receptor associated kinase (IRAK)-M, also known as IRAK-3. IRAK-M is expressed in a number of immune and epithelial cells types, and through its inhibition of pro-inflammatory cytokine production, IRAK-M can regulate immune homeostasis and tolerance in a number of infectious and non-infectious diseases. Furthermore, use of IRAK-M deficient animals has increased our understanding of the importance of IRAK-M in regulating immune responsiveness to a variety of pathogens. Although IRAK-M expression is typically induced through TLR signaling, IRAK-M can also be expressed in response to various endogenous and exogenous soluble factors as well as cell surface and intracellular signaling molecules.This review will focus on clinical scenarios in which expression of IRAK-M is beneficial (as in early sepsis) and those situations where IRAK-M expression is harmful to the host (as in cancer and following bone marrow transplant). There is strong rationale for therapeutic targeting of IRAK-M for clinical benefit. However, effective targeting will require a greater understanding of the transcriptional regulation of this gene.
 ...
PMID:IRAK-M regulation and function in host defense and immune homeostasis. 2139 Feb 43

Infectious complications, sepsis, and multiple organ dysfunction syndrome (MODS) remain important causes for morbidity and mortality in patients who survive the initial trauma. Increasing evidence suggests that genetic variants, particularly single nucleotide polymorphisms (SNPs), are critical determinants for interindividual differences in both inflammatory responses and clinical outcome in sepsis patients. Although the effect of SNPs on sepsis and MODS has been studied in many populations and diseases, this review aimed to summarize the current knowledge on the effect of SNPs on infectious complication specifically in trauma patients. A review of available literature was performed in PubMed database. The following genes have been studied in populations of trauma patients: CD14, HMGB1, IFNG, IL1A, IL1B, IL1RN, IL4, IL6, IL8, IL10, IL17F, IL18, MBL2, MASP2, FCN2, TLR1, TLR2, TLR4, TLR9, TNF, LTA, GR, MYLK, NLRP3, PRDX6, RAGE, HSPA1B, HSPA1L, HSP90, SERPINE1, IRAK1, IRAK3, VEGFA, LY96, ANGPT2, LBP, MicroRNA, and mtDNA. In this review, we discuss the genes of the Pattern Recognition Receptors, Signal Transducing Adaptor Proteins, and Inflammatory Cytokines of the innate immune system. A number of genetic variations have so far been studied in cohorts of trauma patients. Studies are often unique and numbers sometimes small. No definitive conclusions can be reached at this time about the influence of specific sequence variations on outcome in trauma patients.
...
PMID:Effects of Sequence Variations in Innate Immune Response Genes on Infectious Outcome in Trauma Patients: A Comprehensive Review. 2647 37

Sepsis is the leading cause of mortality in intensive care units due to complex inflammatory immune responses and immunosuppression. Recent studies have indicated that the negative regulator of toll like receptors, interleukin-1 receptor-associated kinase 3 (IRAK-3/IRAK-M), serves an important role in immunosuppression during sepsis. In the current study, a cecal ligation puncture model was established in mice using lipopolysaccharide secondary challenge to simulate immunosuppression in sepsis. Peripheral blood mononuclear cells (PBMCs) from this model were then used to evaluate the expression and function of IRAK-M. The results demonstrated that silencing of IRAK-M expression in PBMCs from immunosuppressed mice partially restored the production of pro-inflammatory cytokines. By introducing PBMCs transfected with small-interfering RNA targeting IRAK-M into septic immunosuppressed mice, the survival rate was improved with an increase in splenic CD4+ and CD8+ T cells and a decrease in T cell apoptosis. In conclusion, downregulation of IRAK-M reversed the effects of sepsis on the production of inflammatory cytokines in PBMCs, and improved the survival of septic immunosuppressed mice. These results provide a basis for future studies investigating the immunological mechanisms underlying immune suppression in sepsis.
 ...
PMID:Interleukin-1 receptor-associated kinase 3 downregulation in peripheral blood mononuclear cells attenuates immunosuppression in sepsis. 2943 44

Objective To identify key pathogenic differentially expressed genes and pathways in neutrophils of patients with sepsis. Methods Firstly, we screened and downloaded a total of 143 experimental and 65 control neutrophil samples from Gene Expression Omnibus (GEO) gene expression profile datasets GSE6535, GSE49755, GSE49756, GSE49757. Secondly, we identified differentially expressed genes (DEGs) via corresponding packages in R software. Finally, through intersecting DEGs from every two datasets of those four GEO datasets, we had got 93 DEGs as candidate DEGs, and subsequently conducted gene ontology and pathway enrichment analysis, PPI network analysis and hub gene analysis, using multiple methods containing DAVID, STRING, Cytoscape Apps such as ReactomeFIPlugIn and Cytohubba. Results We had identified most significant hub DEGs, including TLR2, SRC, MMP9, IL1R2, ARRB1, IRAK3, IL18R1, IL18RAP, and STK17B. Besides, we found that some pathogenicity-related pathways and immune-related biological processes were involved in sepsis. The hub genes found by this study might cause sepsis through a variety of signaling pathways and be implicate in the pathogenesis of sepsis. Conclusion These genes may cause the onset and development of sepsis through a variety of signaling pathways.
 ...
PMID:[Identification of differentially expressed genes and pathways changing in neutrophils of patients with sepsis by bioinformatics analysis]. 3129 51