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PubMed2004

Chemoattractants and their receptors in homeostasis and inflammation.

The study of leukocyte migration continues to provide new insights into the regulation of lymphocyte priming in secondary lymphoid organs and effector responses in inflamed tissues. Chemoattractant receptors have always been viewed as facilitators of cell movement into a tissue. This whole concept must now be revised with the discovery of sphingosine 1 phosphate receptors, which control cell exit from lymphoid tissues. The chemoattractants that regulate lymphoid tissue homing are usually different to those that regulate leukocyte recruitment to inflamed tissues. There is evidence, however, of inflammatory pathways of leukocyte recruitment in lymph nodes and, conversely of constitutive pathways in peripheral tissues. Finally, antagonists (or agonists) of chemoattractant receptors and their signalling pathways represent the most attractive strategy for the treatment of a wide range of inflammatory diseases, including allergy.

Animals↗

PubMed2005

Inhibition of IFN-gamma-stimulated proinflammatory cytokines by vasoactive intestinal peptide (VIP) correlates with increased survival of Salmonella enterica serovar typhimurium phoP in murine macrophages.

Vasoactive intestinal peptide (VIP)is a novel Th2 cytokine that has been shown previously to rescue rats and mice from the lethal effect of bacterial lipopolysaccharide (LPS). We report that VIP inhibited production of the proinflammatory cytokines, tumor necrosis factor-alpha(TNF-alpha)and interleukin-1beta (IL-1beta), at the mRNA level and that the inhibitory effect of VIP was maintained when macrophages were cocultured with an immunostimulatory concentration of interferon-gamma (IFN-gamma)(100 U/ml). The concentration of VIP that had optimal inhibitory effect was (1010) M. Furthermore, VIP prevented macrophage killing of a phoP mutant of Salmonella enterica serovar typhimurium, which is usually attenuated for virulence as a result of its inability to survive inside macrophages. However, although the effect of VIP on inducible nitric oxide synthase (iNOS) was less clear, N-monoethyl arginine (NEMA)(an iNOS inhibitor)did not rescue S. typhimurium from IFN- gamma-induced death, in accordance with previous reports that suggest that iNOS is not an important Salmonella killing pathway in macrophages within the first 24 h. VIP is a potent inhibitor of inflammatory pathways that lead to significant pathologic conditions. However, it increases survival of the normally avirulent phoP mutant and is able to inhibit IFN-gamma-stimulated killing of wild-type S. typhimurium in murine macrophages. Thus, VIP inhibits the proinflammatory type 1 response, thus favoring Salmonella survival.

Animals↗

PubMed2006

Lovastatin reduces apoptosis and downregulates the CD40 expression induced by TNF-alpha in cerebral vascular endothelial cells.

Inflammation may be one of the independent risk factors contributing to many neurological diseases. Moreover, there is an emerging body of data indicating that statins may have neuroprotective action. Recent studies suggest that CD40-CD40 ligand (CD40L) system is proven to be an important mediator of several auto-immune and chronic inflammation diseases. To address whether lovastatin produces neuroprotection as a potential novel anti-inflammatory pathway through the inhibition of CD40 expression, we examined the possible effects of lovastatin on expression of CD40, apoptosis, level of nitric oxide (NO) and nitric oxide synthase (NOS) activity induced by tumor necrosis factor alpha (TNF-alpha) in the cerebral vascular endothelial cells (CVECs) involved in cerebrovascular diseases. Preincubation with lovastatin (10(-7), 10(-6) and 10(-5) mol/l) for 24 hours (h) protected CVECs from TNF-alpha-induced decrease of cellular viability. Further, lovastatin inhibited the TNF-alpha-induced increases of NO level, NOS activity, apoptotic cells and CD40 expression in a dose-dependent manner, and anti-CD40 antibody also inhibited the cellular apoptosis induced by TNF-alpha. In conclusion, our data provide evidence to support a direct pro-inflammatory effect of CD40-CD40L signaling pathway in CVECs, and lovastatin possesses an anti-inflammatory effect independent of its lipid-lowering action involved in the cerebrovascular diseases.

Animals↗

PubMed2007

Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases.

BACKGROUND: Leukotrienes derived from the 5-lipoxygenase pathway are proinflammatory lipid mediators that possibly play a role in inflammatory bowel diseases. The expression of 5-lipoxygenase pathway proteins has not previously been examined in colonic mucosa in inflammatory bowel disease. RESULTS: Quantitative immunohistochemical analyses showed that, compared to those of the control subjects (n = 9), colonic biopsies from patients with active inflammatory bowel disease (n = 17) had 3- to 7-fold higher mean counts of cells expressing 5-lipoxygenase (P = 0.03), 5-lipoxygenase-activating protein (P = 0.005), and the leukotriene A(4) hydrolase (P = 0.004), which make up the biosynthetic pathway of the potent neutrophil chemotaxin leukotriene B(4). Immunoexpression of the leukotriene C(4) synthase was unaltered (P > 0.2). The increased representation of leukotriene B(4)-pathway enzymes was associated with higher counts of neutrophils (P = 0.0001), macrophages (P = 0.03), eosinophils (P = 0.0004), CD8(+) T cells (P < 0.001), activated T cells (P < 0.05), and B cells (P < 0.05) but not of mast cells (P > 0.9). These eicosanoid and cellular changes were most marked in the subgroup of patients with ulcerative colitis (n = 9), and were absent in patients with quiescent disease (n = 6). The anomalies in the 5-lipoxygenase pathway were accompanied as expected by more cells immunostaining for cytokine-inducible COX-2 (P = 0.004, n = 17), but this study also revealed a greater number of cells expressing COX-1 in the samples from the patients in the ulcerative colitis subgroup (P = 0.03, n = 9). CONCLUSIONS: The 5-lipoxygenase data provide a cellular basis for increased tissue synthesis of the leukotriene B(4), as reflected in the colonic mucosa and rectal dialysates of patients with active inflammatory bowel disease, which contributes to neutrophil influx and colonic injury. The COX-1/COX-2 data highlight the ambiguous functional role of prostanoid pathways in inflammatory bowel diseases.

Adult↗

PubMed2006

Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway.

Nuclear factor (NF)-kappaB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-alpha activators also reduce NF-kappaB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-kappaB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-alpha-induced decrease in cytosolic I-kappaBalpha protein expression and inhibited the translocation of NF-kappaB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-alpha-induced NF-kappaB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-alpha antagonist. GP extract and Gyp-XLIX (EC(50): 10.1 microM) enhanced PPAR-alpha luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-alpha. Additionally, Gyp-XLIX specifically enhanced PPAR-alpha mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-alpha was demonstrated by the activation of only PPAR-alpha in HEK293 cells transfected with expression vectors for PPAR-alpha, PPAR-beta/delta or PPAR-gamma1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-kappaB activation via a PPAR-alpha-dependent pathway.

Analysis of Variance↗

PubMed2005

The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes.

A novel proteoglycan, proteolysis inducing factor (PIF), is capable of inducing muscle proteolysis during the process of cancer cachexia, and of inducing an acute phase response in human hepatocytes. We investigated whether PIF is able to activate pro-inflammatory pathways in human Kupffer cells, the resident macrophages of the liver, and in monocytes, resulting in the production of pro-inflammatory cytokines. Normal liver tissue was obtained from patients undergoing partial hepatectomy and Kupffer cells were isolated. Monocytes were isolated from peripheral blood. Following exposure to native PIF, pro-inflammatory cytokine production from Kupffer cells and monocytes was measured and the NF-kappaB and STAT3 transcriptional pathways were investigated using electrophoretic mobility shift assays. We demonstrate that PIF is able to activate the transcription factor NF-kappaB and NF-kappaB-inducible genes in human Kupffer cells, and in monocytes, resulting in the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. PIF enhances the expression of the cell surface molecules LFA-1 and CD14 on macrophages. PIF also activates the transcription factor STAT3 in Kupffer cells. The pro-inflammatory effects of PIF, mediated via NF-kappaB and STAT3, are important in macrophage behaviour and may contribute to the inflammatory pro-cachectic process in the liver.

Acute-Phase Reaction↗

PubMed2001

Cocaine activates redox-regulated transcription factors and induces TNF-alpha expression in human brain endothelial cells.

Cocaine abuse is frequently associated with cerebrovascular pathology. Although the cellular and molecular mechanisms of these alterations are not fully understood, they may involve oxidative injury or dysfunction of brain microvascular endothelial cells. To test this hypothesis, total glutathione levels, activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), as well as induction of the TNF-alpha gene expression were determined in human brain microvascular endothelial cells (HBMEC) exposed to cocaine. Exposure of HBMEC to cocaine resulted in a dose-dependent depletion of total glutathione levels. In addition, cocaine markedly activated redox-regulated transcription factors, NF-kappaB and AP-1. Activation of these transcription factors was accompanied by induction of AP-1- or NF-kappaB-dependent transcription, as measured by dual luciferase assay in HBMEC transfected with the AP-1- or NF-kappaB-responsive reporter constructs. Furthermore, HBMEC treatment with cocaine induced a dose-dependent expression of the tumor necrosis factor-alpha (TNF-alpha) gene. These results indicate that exposure to cocaine can trigger inflammatory pathways via activation of redox-sensitive transcription factors and induction of expression of the inflammatory genes in HBMEC. These events may contribute to the cerebrovascular insults observed in cocaine-abused patients.

Brain Chemistry↗

PubMed1997

NF-kappa B as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA.

One of the most challenging issues of anti-inflammatory gene therapy is the complexity of inflammatory pathways. Transcription factor NF-kappa B plays a pivotal role in activation of multiple inflammatory molecules, and therefore represents the logical target for intervention. We evaluated the feasibility of suppressing the inflammatory responses in different cell lines through specific inhibition of NF-kappa B by gene transfer of I kappa B alpha, the naturally occurring intracellular inhibitor of NF-kappa B. The I kappa B alpha overexpressing cells were established using retroviral gene transfer or stable transfection with the wild-type (wt) I kappa B alpha cDNA. In all cell types, overexpression of wt I kappa B alpha resulted in a profound (> 100-fold) increase of the I kappa B alpha message and a moderate (two- to three-fold) increase of the I kappa B alpha protein. The effects of the I kappa B alpha overexpression on the NF-kappa B activation and the inflammatory responses varied significantly in different cell lines. In conditionally immortalized human endometrial stromal cells, overexpression of I kappa B alpha prevented both interleukin-1 (IL-1)-inducible degradation of endogenous I kappa B alpha protein and activation of NF-kappa B. Accordingly, induction of cytokines interleukin-8 (IL-8) and Gro gamma was markedly suppressed. In monocytic THP-1 cells, both lipopolysaccharide (LPS)-inducible degradation of I kappa B alpha and NF-kappa B activation were only partially inhibited by overexpression of exogenous I kappa B alpha cDNA. None the less, the LPS-induced transcription of IL-1 beta and secretion of cytokines interleukin-6 (IL-6) and IL-8 were virtually abolished. In epithelial HT-29 cells, no inflammatory responses were inhibited. These results demonstrate the range of responses in various cell lines to gene transfer of I kappa B alpha and indicate the feasibility of suppression of inflammatory responses in appropriate target cells and their progeny by suppression of NF-kappa B.

Cell Line↗

PubMed2006

Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages.

Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-gamma and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFbetaII receptor, TGF-beta signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF-beta production. On the other hand, a requirement for TGF-beta was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF-beta-dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-gamma, and lipoxin A(4) production, which were also up-regulated by a TGF-beta-dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production.

Animals↗

PubMed2026

Two-sample Mendelian randomization study of gut microbiota and inflammatory proteins: Predictive, preventive, and personalized treatment for migraine.

The human gut microbiota is increasingly recognized as a significant factor in the pathogenesis of migraine, potentially via inflammatory pathways. Identifying specific human gut microbiota components associated with migraines, along with the investigation of particular inflammatory proteins, is essential for advancing primary prediction, targeted prevention, and personalized treatment strategies for migraines. We conducted a two-sample Mendelian randomization study using publicly available summary statistics from genome-wide association studies. Data for 473 human gut microbiota taxa were obtained from the Finnish national health survey conducted by the National Institute for Health and Welfare study (FINRISK, n = 5959 European participants). Genome-wide association study data (https://www.ebi.ac.uk/gwas/) for 91 circulating inflammatory proteins were obtained from 14,824 participants across 11 cohorts using the Olink Target 96 Inflammation panel. Migraine outcome data were obtained from the FinnGen R12 release, with cases defined using ICD-10 code G43. All genome-wide association study analyses were adjusted for sex, age, genotyping batch, and 10 genetic principal components to control population stratification (genomic inflation factors: 1.00–1.05). Inverse variance-weighted Mendelian randomization was the primary analysis method, with Mendelian randomization-Egger, weighted median, and mode-based methods as sensitivity analyses. Two-step Mendelian randomization mediation analysis quantified the proportion of the effects of human gut microbiota on migraine that are mediated through inflammatory proteins. Thirty-seven bacterial genera were found to be associated with migraine using the inverse variance-weighted method. Of these, 18 genera exhibited a negative association, while 19 genera demonstrated a positive association with migraine risk. Additionally, eight inflammatory proteins were found to increase the risk of migraine. Among human gut microbiota, four were observed to reduce inflammatory protein levels, whereas another four were associated with increased inflammatory protein levels. Additionally, five gut microbiota were identified to influence migraine through inflammatory proteins in both Mendelian randomization analyses. Specifically, Actinobacteria, Brachyspiraceae, CAG-269 sp001915995, and Paraglaciecola were found to affect migraine outcomes via inflammatory proteins, with mediation proportions of 12%, 19%, 15.5%, and 6.7%, respectively. Lawsonibacter sp002161175 was identified to influence migraine risk through Oncostatin-M and SLAM, with mediation proportions of 15.6% and 11.3%, respectively. Our study elucidated the role of specific human gut microbiota alterations in the pathogenesis of migraine and highlighted the mediating effects of inflammatory proteins. Targeting these particular human gut microbiota alterations offers a promising strategy for predictive, preventive, and personalized medicine in migraine management, resulting in substantial clinical advancements.

causality↗

PubMed2005

[Auto-inflammatory syndromes].

Auto-inflammatory syndromes are a group of hereditary diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever, which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases, as underlied by a specific inflammatory pathway. This new group of diseases has already opened new avenues in our understanding of the inflammatory response.

Autoimmune Diseases↗

PubMed2004

In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain.

The capacity of non-pathogenic enteric bacteria to induce a pro-inflammatory response is under debate in terms of its effect on the symbiosis between the mammalian host and its commensal gut microflora. Activation of NF-kappaB and induction of interleukin-8 (IL-8) and CCL-20 by the commensal Escherichia coli strain MG1655 were first studied in vitro in the human intestinal epithelial cell (IECs) lines HT29-19A and Caco-2, transfected or not with plasmids encoding dominant negative Toll-like receptor (TLR) 5 and myeloid differentiation factor-88 (MyD88) adaptor protein. The response of enterocytes in situ was then assessed using murine ileal biopsies mounted in Ussing chambers. Commensal E. coli induced NF-kappaB DNA binding, NF-kappaB transcriptional activity, CCL-20 expression, and IL-8 secretion in the human IEC lines. E. coli MG1655 flagellin was necessary and sufficient to trigger this pro-inflammatory pathway via its interaction with TLR5 and the subsequent recruitment of the adaptor protein MyD88. Following epithelial cell polarization, signaling could be induced by live E. coli and flagellin on the apical side of HT29-19A. The in vivo relevance of our findings was confirmed, because immunohistochemical staining of murine ileum demonstrated expression of TLR5 in the apical part of enterocytes in situ. Furthermore, flagellin added on the mucosal side of murine ileal biopsies mounted in Ussing chambers induced a basolateral production of KC, a functional murine homolog of human IL-8. These findings provide strong evidence that flagellin released by flagellated commensal bacteria in the intestinal lumen can induce a pro-inflammatory response in enterocytes in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Triacylglycerol-rich lipoprotein-gene interactions in endothelial cells.

Lipoproteins such as LDL (low-density lipoprotein) and oxidized LDL have potentially adverse effects on endothelial cells due to their ability to activate pro-inflammatory pathways regulated via the transcription factor NF-kappaB (nuclear factor kappaB). Triacylglycerol-rich lipoproteins (the chylomicrons, very-low-density lipoprotein and their respective remnant particles) have also been implicated in the induction of a pro-inflammatory phenotype and up-regulation of adhesion molecule expression. Although early studies supported the proposal that LPL (lipoprotein lipase)-mediated hydrolysis of TRLs (triglyceride-rich lipoproteins) at the endothelium could activate the NFkappaB pathway, more recent studies provide evidence of pro- and anti-inflammatory responses when cells are exposed to fatty acids or TRL particles. A large number of genes are up- and down-regulated when cells are exposed to TRL, with the net effect reflecting receptor- and nonreceptor-mediated pathways that are activated or inhibited depending on fatty acid type, the lipid and apolipoprotein composition of the TRL and the presence or absence of LPL. Early concepts of TRL particles as essentially pro-inflammatory stimuli to the endothelium provide an overly simplistic view of their impact on the vascular compartment.

Animals↗

PubMed2003

Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo.

Inflammation must be inhibited in order to treat, e.g., sepsis or autoimmune diseases or must be selectively enhanced to improve, for example, immunotherapies of tumors or the development of vaccines. Predictable enhancement of inflammation depends upon the knowledge of the "natural" pathways by which it is down-regulated in vivo. Extracellular adenosine and A(2A) adenosine (purinergic) receptors were identified recently as anti-inflammatory signals and as sensors of excessive inflammatory tissue damage, respectively (Ohta A and Sitkovsky M, Nature 2001;414:916-20). These molecules may function as an important part of a physiological "metabolic switch" mechanism, whereby the inflammatory stimuli-produced local tissue damage and hypoxia cause adenosine accumulation and signaling through cyclic AMP-elevating A(2A) adenosine receptors in a delayed negative feedback manner. Patterns of A(2A) receptor expression are activation- and differentiation-dependent, thereby allowing for the "acquisition" of an immunosuppressive "OFF button" and creation of a time-window for immunomodulation. Identification of A(2A) adenosine receptors as "natural" brakes of inflammation provided a useful framework for understanding how tissues regulate inflammation and how to enhance or decrease (engineer) inflammation by targeting this endogenous anti-inflammatory pathway. These findings point to the need of more detailed testing of anti-inflammatory agonists of A(2A) receptors and create a previously unrecognized strategy to enhance inflammation and targeted tissue damage by using antagonists of A(2A) receptors. It is important to further identify the contributions of different types of immune cells at different stages of the inflammatory processes in different tissues to enable the "tailored" treatments with drugs that modulate the signaling through A(2A) purinergic receptors.

Adenosine↗

PubMed2006

On the enigma of pain and hyperalgesia: A molecular perspective.

Pain is a common symptom of injuries and inflammatory-related conditions. The perception of pain, commonly known as nociception, depends on integrated receptors and molecular pathways. Inflammatory mediators are involved in the genesis, persistence, and severity of pain. Noxious stimuli can trigger a cascade of inflammatory loops that feedback onto sensory modalities and domains of the CNS, in an attempt to alert the brain of deregulated homeostasis. Understanding the mechanisms of pain continue to make nociception and hyperalgesia a burgeoning field of research.

Animals↗

PubMed2003

Factor X inhibitors.

Factor X plays a central role in coagulation, being the point of convergence of the extrinsic and intrinsic pathways of blood clotting. It may also act as one of the links between the coagulation and inflammatory pathways. These findings suggest that factor X may represent an attractive target for a new antithrombotic drug. Indeed, a factor X inhibitor, fondaparinux, has already been approved for clinical use to prevent post-operative deep vein thrombosis. Factor X inhibitors are also being evaluated for use in the treatment of the acute coronary syndromes, pulmonary embolism and deep vein thrombosis. Oral factor X inhibitors are also being developed, which may be of use in the outpatient prevention and/or treatment of stroke and thromboembolism.

Anticoagulants↗

PubMed2025

The X-Linked TLR7 rs179008 T Allele Is Associated with an Increased Risk of Severe Multisystem Inflammatory Syndrome in Children/Kawasaki-like Syndrome in SARS-CoV-2-Infected Boys.

The X-linked TLR7 rs179008 T allele has been associated with altered antiviral immunity. Given their shared inflammatory pathways and higher pediatric mortality rates in Brazil during the pandemic, we investigated their association with multisystem inflammatory syndrome in children (MIS-C) together with Kawasaki disease (KS) following SARS-CoV-2 infection. A cross-sectional study (2021-2022) analyzed 73 hospitalized children (<13 years) with confirmed COVID-19. Genotyping for TLR7 rs179008, TLR8 (rs3764879, rs2407992), and TLR3 rs3775291 was performed via PCR and Sanger sequencing. MIS-C/KS cases were identified using CDC criteria, with severity classified by the need for ICU care. Statistical analysis included Fisher's exact test and relative risk (RR) calculations. Hemizygous boys carrying the TLR7 T allele had a 1.87-fold higher risk of MIS-C/KS (p = 0.007) and a 1.75-fold increased risk of severe or critical outcomes. The T allele frequency was 2.6× higher in MIS-C/KS cases versus other COVID-19 presentations. All fatalities occurred in boys (3/8 MIS-C cases) with one T-allele carrier. No associations were found for TLR8 or TLR3 variants. The TLR7 rs179008 T allele is a potential genetic risk factor for severe post-COVID-19 inflammatory syndromes in boys, likely due to impaired immune signaling. These findings highlight its utility as a biomarker for risk stratification in pediatric populations.

Humans↗

PubMed2000

Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin.

Recent evidence suggests a role for activin A, and its binding protein, follistatin, in inflammatory pathways. However, whether activin is released systemically during inflammation is not known. In this study, a release of activin A into the circulation occurred in sheep within 1 hour of injection of lipopolysaccharide. This rapid peak in activin A preceded the release of the key inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6. Follistatin release into the circulation occurred some 4 hours after the peak of activin A and continued out to 24 hours from lipopolysaccharide treatment. These data are the first to document a circulatory response of activin A to an inflammatory stimulus, and together with previous findings, suggest that activin A may have both pro- and anti-inflammatory actions in regulating cytokine-driven pathways.

Activins↗