Role of α2-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice

2002 ◽  
Vol 283 (1) ◽  
pp. R218-R226 ◽  
Author(s):  
Alexander V. Gourine ◽  
Valery N. Gourine ◽  
Yohannes Tesfaigzi ◽  
Nathalie Caluwaerts ◽  
Fred Van Leuven ◽  
...  
Keyword(s):  
Mrna Level ◽  
Physiological Role ◽  
Mrna Levels ◽  
Wild Type ◽  
Cytokine Responses ◽  
Α2 Macroglobulin ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

α2-Macroglobulin (α2M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). To define the role of α2M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in α2M (α2M −/−) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1β, IL-6, and TNF-α and hepatic TNF-α mRNA level during fever in α2M −/− mice were compared with those in wild-type control mice. The α2M −/− mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-α, but not IL-1β or IL-6, was significantly lower (by 58%) in the α2M −/− mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-α mRNA levels between α2M −/− and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) α2M is important for the normal development of LPS-induced fever and 2) a putative mechanism of α2M involvement in fever is through the inhibition of TNF-α clearance. These findings indicate a novel physiological role for α2M.

scholarly journals Platelet-Endothelial Interactions in Inflamed Mesenteric Venules

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1318-1324 ◽  
Author(s):  
Paul S. Frenette ◽  
Caitlin Moyna ◽  
Daqing W. Hartwell ◽  
John B. Lowe ◽  
Richard O. Hynes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wild Type ◽  
Membrane Glycoproteins ◽  
Active Function ◽  
Tnf Α ◽  
Thrombin Activation ◽  
Selectin Ligand ◽  
Factor Α ◽  
Necrosis Factor

Abstract The selectins are membrane glycoproteins promoting adhesive events between leukocytes, platelets, and endothelial cells. We have previously demonstrated that platelets roll on P-selectin expressed on stimulated endothelium. In this study, we wished to examine the function of both the platelet and endothelial selectins, P- and E-selectins, in mediating platelet-endothelial interactions during inflammation. We demonstrate, using intravital microscopic examination of venules inflamed with tumor necrosis factor-α (TNF-α), that resting platelets interact with both P- and E-selectins and that the leukocyte α(1,3)fucosyltransferases FucT IV and FucT VII do not provide platelets with selectin ligand activity. We also show that after thrombin activation of wild-type (+/+) platelets, platelet P-selectin can mediate interactions on a TNF-α–inducible endothelial ligand. To evaluate the potential role of platelet P-selectin in the recruitment of leukocytes to inflammatory sites, we reconstituted the bone marrow of mice deficient in both P- and E-selectins (P/E−/−) with wild-type (+/+) or P-selectin–deficient (P−/−) bone marrow containing megakaryocytic precursors. Providing +/+ platelets to P/E−/− mice by bone marrow transplantation did not rescue the immunodeficient phenotype, suggesting that platelet P-selectin does not have an active function in the recruitment of leukocytes into inflammatory sites. To participate in inflammatory or hemostatic responses, platelets may use the endothelial selectins.

The Role of Tumor Necrosis Factor-α (TNF-α) Polymorphisms in Gastric Cancer: a Meta-Analysis

2021 ◽  
Author(s):  
Maryam Gholamalizadeh ◽  
Samaneh Mirzaei Dahka ◽  
Hadi Sedigh Ebrahim-Saraie ◽  
Mohammad Esmail Akbari ◽  
Azam Pourtaheri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Meta Analysis ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis

2001 ◽  
Vol 280 (5) ◽  
pp. F777-F785 ◽  
Author(s):  
Guangjie Guo ◽  
Jeremiah Morrissey ◽  
Ruth McCracken ◽  
Timothy Tolley ◽  
Helen Liapis ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tumor Necrosis Factor ◽  
Renal Fibrosis ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
Tnf Α ◽  
Factor Α ◽  
Tgf Β1 ◽  
Necrosis Factor

Angiotensin II upregulates tumor necrosis factor-α (TNF-α) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-α receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT1a or the TNF-α receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (Vvint) in the C57BI/6 wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% ( P < 0.005) or in the TNFR1/TNFR2 KO to 22.3 ± 2.1% ( P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further decreased to 15.2 ± 3.7% ( P < 0.01) by enalapril compared with no treatment. The induction of TNF-α mRNA and transforming growth factor-β1 (TGF-β1) mRNA in the kidney with UUO was significantly blunted in the AT1a or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-α and TGF-β1 mRNA and their proteins to near normal levels. Also, α-smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT1a or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-α systems individually leads to partial blunting of fibrosis. Incapacitating both systems, by using a combination of genetic and pharmacological means, further inhibited interstitial fibrosis and tubule atrophy in obstructive nephropathy.

Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding

1999 ◽  
Vol 112 (21) ◽  
pp. 3603-3617 ◽  
Author(s):  
J. Schlondorff ◽  
C.P. Blobel
Keyword(s):  
Tumor Necrosis ◽  
Ectodomain Shedding ◽  
Membrane Glycoproteins ◽  
Tnf Α ◽  
Disintegrin Domain ◽  
Protein Ectodomain Shedding ◽  
Integrin Ligands ◽  
Factor Α ◽  
Necrosis Factor

Metalloprotease-disintegrins (ADAMs) have captured our attention as key players in fertilization and in the processing of the ectodomains of proteins such as tumor necrosis factor (α) (TNF(α)), and because of their roles in Notch-mediated signaling, neurogenesis and muscle fusion. ADAMs are integral membrane glycoproteins that contain a disintegrin domain, which is related to snake-venom integrin ligands, and a metalloprotease domain (which can contain or lack a catalytic site). Here, we review and critically discuss current topics in the ADAMs field, including the central role of fertilin in fertilization, the role of the TNF(α) convertase in protein ectodomain processing, the role of Kuzbanian in Notch signaling, and links between ADAMs and processing of the amyloid-precursor protein.

The role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in Hirschsprung associated enterocolitis

2020 ◽  
Author(s):  
Feng Chen ◽  
Xiaoyu Wei ◽  
Xiaohua Chen ◽  
Lei Xiang ◽  
Xinyao Meng ◽  
...  
Keyword(s):  
Western Blotting ◽  
Mrna Level ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Wild Type ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Phosphorylated Stat3 ◽  
Morphology Changes

Abstract Background To investigate the role and the underlying mechanism of the α7nAChR-mediated cholinergic anti-inflammatory pathway in the pathogenesis of Hirschsprung(HSCR) associated enterocolitis（HAEC）. Methods Experimental group:twenty-one-day-old Ednrb-/- mice were selected (n=10), with comparable-age wild type(Ednrb+/+) mice controls (n=10). Intestinal samples were collected. The experimental colons were divided into narrow and dilated segments according to morphology changes. The control colons were divided into distal and proximal segments.Colon HE staining was used to judge HAEC.Acetylcholine levels in colon was measured using enzyme-linked immunosorbent assays. Detected phosphorylated Jak2 (p-Jak2), Jak2, phosphorylated Stat3 (p-Stat3), Stat3, phosphorylated IκBα (p-IκBα) and IκBα were studied by Western blotting; mRNA levels of Jak2, Stat3, and IκBα were detected by RT-qPCR. Results Colon HE staining indicated that HAEC mainly occured in the dilated segments of HSCR mice (Ednrb-/- mice) (EDNRB-P).Acetylcholine content in EDNRB-P was significantly lower than that in the narrow segments (EDNRB-D) (P<0.05). Western blotting showed that the Jak2, p-Jak2, Stat3 and p-Stat3 levels in EDNRB-D were significantly higher than those in EDNRB-P (P<0.05). The p-IκBα and IκBα levels in EDNRB-P were significantly higher than those in EDNRB-D(P<0.05). The mRNA levels of Jak2 and Stat3 in EDNRB-D were higher than those in EDNRB-P, but the IκBα mRNA level was significantly lower than that in EDNRB-P (P<0.05). Conclusions During HAEC, the inflammation in the dilated segment was more severe ,while in the narrow segment there was no obvious inflammatory reaction and the content of acetylcholine was higher, which was associated with the α7nAChR-mediated cholinergic anti-inflammatory pathway.

Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation

2001 ◽  
Vol 280 (4) ◽  
pp. L659-L665 ◽  
Author(s):  
Finn Finsnes ◽  
Torstein Lyberg ◽  
Geir Christensen ◽  
Ole H. Skjønsberg
Keyword(s):  
Tumor Necrosis Factor ◽  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mrna Level ◽  
Mrna Levels ◽  
Proinflammatory Mediators ◽  
Factor Α ◽  
Necrosis Factor

Endothelin (ET)-1 has been launched as an important mediator in bronchial asthma, which is an eosinophilic airway inflammation. However, the interplay between ET-1 and other proinflammatory mediators during the development of airway inflammation has not been elucidated. We wanted to study 1) whether the production of ET-1 precedes the production of other proinflammatory mediators and 2) whether ET-1 stimulates the production of these mediators within the airways. These hypotheses were studied during the development of an eosinophilic airway inflammation in rats. The increase in ET-1 mRNA level in lung tissue preceded the increase in mRNA levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-8. Treatment of the animals with the ET receptor antagonist bosentan resulted in a substantial decrease in the concentrations of tumor necrosis factor-α, IL-4, IL-1β, interferon-γ, and ET-1 in bronchoalveolar lavage fluid. In conclusion, the synthesis of ET-1 as measured by increased mRNA level precedes the synthesis of other proinflammatory cytokines of importance for the development of an eosinophilic airway inflammation, and ET antagonism inhibits the production of these mediators within the airways. Whether treatment with ET antagonists will prove beneficial for patients with eosinophilic airway inflammations like bronchial asthma is not yet known.

Association Between Tumor Necrosis Factor-α Gene Polymorphism and Sasang Constitution in Cerebral Infarction

2005 ◽  
Vol 33 (04) ◽  
pp. 547-557 ◽  
Author(s):  
Jae-Young Um ◽  
Jae-Heung Lee ◽  
Jong-Cheon Joo ◽  
Kyung-Yo Kim ◽  
Eun-Hee Lee ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cerebral Infarction ◽  
Promoter Region ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Sasang Constitution ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

During the last decade, a growing corpus of evidence has indicated an important role of cytokines in the development of brain damage following cerebral ischemia. Tumor necrosis factor-α (TNF-α), a potent immunomodulator and pro-inflammatory cytokine, has been implicated in many pathological processes. In this study, we examined whether promoter region polymorphism in the TNF-α gene at position –308 affects the odds of cerebral infarction (CI) and whether genetic risk is enhanced by Sasang constitutional classification. Two hundred and twelve CI patients and 610 healthy controls were genotyped and determined according to Sasang constitutional classification. A significant decrease was found for the TNF-α A allele in CI patients compared with controls ( p = 0.033, odds ratio, OR: 0.622). However, there was no significant association between TNF-α polymorphism and Sasang constitution in CI patients. Our finding suggests that TNF-α promoter region polymorphism is responsible for susceptibility to CI in Koreans.

scholarly journals Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular β-epithelial Na+ channel

2020 ◽  
Vol 318 (4) ◽  
pp. H1018-H1027 ◽  
Author(s):  
Jeremy W. Duncan ◽  
Subhi Talal Younes ◽  
Emily Hildebrandt ◽  
Michael J. Ryan ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Function ◽  
Mapk Signaling ◽  
Pregnant Rats ◽  
Tnf Α ◽  
Factor Α ◽  
Placental Ischemia ◽  
Necrosis Factor

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of β-epithelial Na+ channel (βENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, βENaC is an essential signaling element in transduction of pressure-induced (aka “myogenic”) constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular βENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular βENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of βENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell βENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1–100 ng/mL) for 16–24 h. TNF-α reduced βENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated βENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced βENaC-mediated vascular function. NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular β-epithelial sodium channel (βENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced βENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.

scholarly journals Accelerated Neutrophil Apoptosis in Mice Lacking A1-a, a Subtype of the bcl-2–related A1 Gene

1998 ◽  
Vol 188 (11) ◽  
pp. 1985-1992 ◽  
Author(s):  
Azumi Hamasaki ◽  
Fujiro Sendo ◽  
Keiko Nakayama ◽  
Noriko Ishida ◽  
Izumi Negishi ◽  
...  
Keyword(s):  
Neutrophil Apoptosis ◽  
Spontaneous Apoptosis ◽  
Wild Type ◽  
Apoptosis Inhibition ◽  
Blood Neutrophils ◽  
Factor Α ◽  
Necrosis Factor

To elucidate the role of A1, a new member of the Bcl-2 family of apoptosis regulators active in hematopoietic cell apoptosis, we established mice lacking A1-a, a subtype of the A1 gene in mice (A1-a−/− mice). Spontaneous apoptosis of peripheral blood neutrophils of A1-a−/− mice was enhanced compared with that of either wild-type mice or heterozygous mutants (A1-a+/− mice). Neutrophil apoptosis inhibition induced by lipopolysaccharide treatment in vitro or transendothelial migration in vivo observed in wild-type mice was abolished in both A1-a−/− and A1-a+/− animals. On the other hand, the extent of tumor necrosis factor α–induced acceleration of neutrophil apoptosis did not differ among A1-a−/−, A1-a+/−, and wild-type mice. The descending order of A1 mRNA expression was wild-type, A1-a+/−, and A1-a−/−. Taken together, these results suggest that A1 is involved in inhibition of certain types of neutrophil apoptosis.

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