NF-κB- and C/EBPβ-driven Interleukin-1β Gene Expression and PAK1-mediated Caspase-1 Activation Play Essential Roles in Interleukin-1β Release from Helicobacter pylori Lipopolysaccharide-stimulated Macrophages
Helicobacter pylori is a Gram-negative microaerophilic bacterium that causes chronic gastritis, peptic ulcer, and gastric carcinoma. Interleukin-1beta (IL-1beta) is one of the potent proinflammatory cytokines elicited by H. pylori infection. We have evaluated the role of H. pylori lipopolysaccharide (LPS) as one of the mediators of IL-1beta release and dissected the signaling pathways leading to LPS-induced IL-1beta secretion. We demonstrate that both the NF-kappaB and the C/EBPbeta-binding elements of the IL-1beta promoter drive LPS-induced IL-1beta gene expression. NF-kappaB activation requires the classical TLR4-initiated signaling cascade leading to IkappaB phosphorylation as well as PI-3K/Rac1/p21-activated kinase (PAK) 1 signaling, whereas C/EBPbeta activation requires PI-3K/Akt/p38 mitogen-activated protein (MAP) kinase signaling. We observed a direct interaction between activated p38 MAP kinase and C/EBPbeta, suggesting that p38 MAPK is the immediate upstream kinase responsible for activating C/EBPbeta. Most important, we observed a role of Rac1/PAK1 signaling in activation of caspase-1, which is necessary for maturation of pro-IL-1beta. H. pylori LPS induced direct interaction between PAK1 and caspase-1, which was inhibited in cells transfected with dominant-negative Rac1. PAK1 immunoprecipitated from lysates of H. pylori LPS-challenged cells was able to phosphorylate recombinant caspase-1, but not its S376A mutant. LPS-induced caspase-1 activation was abrogated in cells transfected with caspase-1(S376A). Taken together, these results suggested a role of PAK1-induced phosphorylation of caspase-1 at Ser376 in activation of caspase-1. To the best of our knowledge our studies show for the first time that LPS-induced Rac1/PAK1 signaling leading to caspase-1 phosphorylation is crucial for caspase-1 activation. These studies also provide detailed insight into the regulation of IL-1beta gene expression by H. pylori LPS and are particularly important in the light of the observations that IL-1beta gene polymorphisms are associated with increased risk of H. pylori-associated gastric cancer.
"Serum lipopolyaccharides originate from the gastrointestinal tract and their levels increase after eating a meal rich of lipids. H. pylori gastritis and its role in mucosal activation of innate immunity and upregulation of IL-1β is also suggested in the pathogenesis of IR (25). H.pylori gastritis and its effects on ghrelin may also affect appetite and insulin sensitivity (26). "
[Show abstract][Hide abstract] ABSTRACT: Background: The association of HP and insulin resistance degree (IR) has not been evaluated in the diabetic patients so far. In this study, we evaluated the association between HP seropositivity and the homeostatic model assessment for insulin resistance (HOMA-IR) in diabetic patients. Methods: In this study, 211 diabetic patients admitted to the endocrinology clinic of Shahid Beheshti Hospital of Qom for routine diabetic check-ups were evaluated. The patients were divided into HP+ and HP- groups based on the seropositivity of helicobacter pylori IgG antibody. The serum H. pylori IgG antibody, blood sugar, serum insulin, HbA1c, LDL, HDL, cholesterol, triglyceride, HOMA-IR and BMI were measured. Seropositivity for H. pylori was detected based on the serum titers of >30 AU/mL. Results: We found that serum insulin (HP-=6.97±5.64 vs. HP+=10.12±7.72, P=0.002) and insulin resistance degree (HP-=3.160±3.327 vs. HP+=4.484±3.781, P=0.013) is significantly higher in HP+ group. We also found that there is no significant difference between these groups according to the short-term or the long-term indices of glycemic control as well as most of the diabetic risk factors or complications. The treatment type was also not significantly different between these groups. Conclusion: It seems that the HP+ diabetic patients require higher levels of serum insulin to reach the same degree of glycemic control compared to the HP- ones.
Keywords: Keywords: Diabetes, Helicobacter pylori, Insulin Resistance,
Caspian Journal of Internal Medicine 05/2014; Volume 5, Number 3 (5-2014)(3).
"ti - vate both signals , increase the level of the precursor IL - 1b protein , and activate the IPAF inflammasome , leading to the maturation of IL - 1b in primary rat astrocytes . The regulation of proeIL - 1b expression by transcription factor , nuclear factor kappa - light - chain - enhancer of activated B cells ( NFkB ) , is well established ( Basak et al . , 2005 ) , and NFkB is known to be activated by fatty acids , such as PA or a high - fat diet ( Wang et al . , 2012 ) . In support of this , we observed that NFkB expression in the astrocytes is increased on PA treatment ( Supplementary Fig . 6 ) and inhibiting NFkB significantly reduced the mRNA level of proeIL - 1b ( Supplementary Fig . 7 ) "
[Show abstract][Hide abstract] ABSTRACT: Inflammatory response has been strongly implicated in the pathogenesis of numerous diseases, including Alzheimer's disease (AD). However, little is known about the molecular mechanisms initiating the generation of inflammatory molecules in the central nervous system, such as interleukin-1β (IL-1β). Previously we identified that palmitate can induce primary astrocytes to produce cytokines, causing AD-like changes in primary neurons. Here we investigated and identified that palmitate induced the activation of ice protease-activating factor (IPAF)-apoptosis-associated speck-like protein containing a caspase activation and recruitment domains (CARD) (ASC) inflammasome in astrocytes leading to the maturation of IL-1β, thereby implicating that not only pathogen-related factors can activate the IPAF-ASC inflammasome. Moreover, downregulating IPAF (which was found to be regulated by cAMP response element-binding protein) in astrocytes through silencing to decrease IL-1β secretion from the astrocytes reduced the generation of amyloid-β42 by primary neurons. Furthermore, the expression levels of IPAF and ASC were found significantly elevated in a subgroup of sporadic AD patients, suggesting an involvement of the IPAF-ASC inflammasome in the inflammatory response associated with AD, and thus could be a potential therapeutic target for AD.
Neurobiology of aging 09/2013; 35(2). DOI:10.1016/j.neurobiolaging.2013.08.016 · 5.01 Impact Factor
"Moreover, the Rac1 interaction partner LIM kinase has been proposed to signal to caspase-1 . Also, an interaction between the Rac1 effector “p21 activated kinase 1” and caspase-1 has been suggested . Further studies examining the links between Rac1 and inflammasomes are required to fully understand their interaction in bacterial infections. "
[Show abstract][Hide abstract] ABSTRACT: Chlamydophila pneumoniae causes acute respiratory tract infections and has been associated with development of asthma and atherosclerosis. The production of IL-1β, a key mediator of acute and chronic inflammation, is regulated on a transcriptional level and additionally on a posttranslational level by inflammasomes. In the present study we show that C. pneumoniae-infected human mononuclear cells produce IL-1β protein depending on an inflammasome consisting of NLRP3, the adapter protein ASC and caspase-1. We further found that the small GTPase Rac1 is activated in C. pneumoniae-infected cells. Importantly, studies with specific inhibitors as well as siRNA show that Rac1 regulates inflammasome activation in C. pneumoniae-infected cells. In conclusion, C. pneumoniae infection of mononuclear cells stimulates IL-1β production dependent on a NLRP3 inflammasome-mediated processing of proIL-1β which is controlled by Rac1.
PLoS ONE 01/2012; 7(1):e30379. DOI:10.1371/journal.pone.0030379 · 3.23 Impact Factor
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