scholarly journals The role of endothelial PI3Kγ activity in neutrophil trafficking

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 150-157 ◽  
Author(s):  
Kamal D. Puri ◽  
Teresa A. Doggett ◽  
Ching-Yu Huang ◽  
Jason Douangpanya ◽  
Joel S. Hayflick ◽  
...  
Keyword(s):  
Critical Role ◽  
Fold Increase ◽  
Necrosis Factor Alpha ◽  
Catalytic Subunits ◽  
Injury Model ◽  
Lung Injury Model ◽  
Factor Alpha ◽  
Phosphoinositide 3 Kinase

Phosphoinositide 3-kinase gamma (PI3Kγ) in neutrophils plays a critical role in the directed migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3Kγ activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class-Ib PI3K function in neutrophils of p110γ–/– mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in wild-type (WT) neutrophil attachment to and 17-fold increase in rolling velocities on p110γ–/– microvessels in vivo in response to tumor necrosis factor alpha (TNFα). This alteration in adhesion was further augmented by a deficiency in p110δ, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin–mediated adhesion in p110γ–/– mice was impaired by more than 95%, but no defect in nuclear factor kappa B (NF-κB)–induced gene expression was observed. These findings suggest a previously unrecognized partnership between class-I PI3Ks expressed in leukocytes and endothelium, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation.

The Role of Endothelial PI3Kγ Activity in Neutrophil Trafficking.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3891-3891
Author(s):  
Thomas G. Diacovo ◽  
Teresa A. Doggett ◽  
Ching-Yu Huang ◽  
Jason Douangpanya ◽  
Joel Hayflick ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Critical Role ◽  
Fold Increase ◽  
Catalytic Subunits ◽  
Directed Migration ◽  
Injury Model ◽  
Lung Injury Model ◽  
Phosphoinositide 3 Kinase

Abstract Phosphoinositide 3-kinase gamma (PI3Kγ) in neutrophils plays a critical role in the directed-migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3Kγ activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class Ib PI3K function in neutrophils of p110γ−/− mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in WT neutrophil attachment to and 17-fold increase in rolling velocities on p110γ−/− microvessels in vivo in response to TNFα. This alteration in adhesion was further augmented by a deficiency in p110δ, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin-mediated adhesion in p110gamma]−/− mice was impaired by > 95%, but no defect in NF-κB-induced gene expression was observed. These findings suggest a previously unrecognized partnership between class I PI3Ks expressed in leukocytes and endothelium, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation.

scholarly journals Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
T. Secher ◽  
F. Rodrigues Coelho ◽  
N. Noulin ◽  
A. Lino dos Santos Franco ◽  
V. Quesniaux ◽  
...  
Keyword(s):  
Contractile Response ◽  
Ex Vivo ◽  
Adaptor Protein ◽  
Respiratory Pattern ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Bacterial Lipopolysaccharides ◽  
Necrosis Factor

Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.

scholarly journals HAEMATOCOCCUS PLUVIALIS EXTRACT PROMOTING THE RECOVERY OF MEMORY IMPAIRMENT IN ALZHEIMER’S RATS: ANTI-INFLAMMATORY AND ANTIAPOPTOTIC EFFECTS

2016 ◽  
Vol 9 (9) ◽  
pp. 171
Author(s):  
Farouk Kamel Elbaz ◽  
Hanan F Aly ◽  
Wagdy Kb Khalil ◽  
Gamila H Ali ◽  
Hoda F Booles
Keyword(s):  
Oxidative Stress ◽  
Haematococcus Pluvialis ◽  
Lipid Peroxide ◽  
B Cell Lymphoma ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Phosphoinositide 3 Kinase ◽  
Protein Kinase Akt

ABSTRACTObjective: The present study was conducted to investigate the role of Haematococcus pluvialis extract against oxidative damage, the inflammatory,and apoptotic impacts characterizing the neurodegenerative disorders.Methods: Oxidative stress, B-cell lymphoma 2, brain-derived neurotrophic factor, the inflammation, apoptotic and antiapoptotic impacts in Alzheimer’sdisease (AD) rats were determined through assessment of glutathione reduced (GSH), GSH peroxidase (GPx), lipid peroxide (malondialdehyde), thecytokines level such as tumor necrosis factor-alpha (TNF-α), interleukins (IL-6 and IL-1β), and macrophage inflammation protein (MIP1α) in AD rats.Moreover, the expression of phosphoinositide 3-kinase (PI3K) and serine-threonine protein kinase (Akt) genes regulating the apoptosis in AD ratswas measured.Results: The results revealed that levels of TNF-α, IL-6, IL-1β, and MIP1α were significantly increased in AD rats. Moreover, the expression of PI3Kand Akt genes was downregulated which it was coincided with the increase of apoptosis in AD rats. On the other hand, treatment of AD rats withH. pluvialis extract decreased the oxidative stress of AD in the form of prevention the inflammatory and apoptotic impacts.Conclusion: H. pluvialis could be used for ameliorating AD due to its role in decreases the oxidative stress of AD in the form of prevention theinflammatory and apoptotic impacts. H. pluvialis is a very attractive candidate for uses against neurodegenerative disorders that are caused byincreases oxidative stress inducing neuroinflammation and apoptosis.Keywords: Haematococcus pluvialis, Oxidative stress, Inflammation biomarkers, Apoptotic and antiapoptotic impacts.

scholarly journals In Vivo Regulation of Replicative Legionella pneumophila Lung Infection by Endogenous Interleukin-12

1998 ◽  
Vol 66 (1) ◽  
pp. 65-69 ◽  
Author(s):  
J. K. Brieland ◽  
D. G. Remick ◽  
M. L. LeGendre ◽  
N. C. Engleberg ◽  
J. C. Fantone
Keyword(s):  
Legionella Pneumophila ◽  
Lung Infection ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin 12 (IL-12) in modulating intrapulmonary growth of Legionella pneumophila was assessed by using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophilacells per mouse) resulted in induction of IL-12, which preceded clearance of the bacteria from the lung. Inhibition of endogenous IL-12 activity, via administration of IL-12 neutralizing antiserum, resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection (compared to untreated L. pneumophila-infected mice). Because IL-12 has previously been shown to modulate the expression of cytokines, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10, which regulate L. pneumophila growth, immunomodulatory effects of endogenous IL-12 on intrapulmonary levels of these cytokines during replicative L. pneumophila lung infection were subsequently assessed. Results of these experiments demonstrated that TNF-α activity was significantly lower, while protein levels of IFN-γ and IL-10 in the lung were similar, in L. pneumophila-infected mice administered IL-12 antiserum, compared to similarly infected untreated mice. Together, these results demonstrate that IL-12 is critical for resolution of replicativeL. pneumophila lung infection and suggest that regulation of intrapulmonary growth of L. pneumophila by endogenous IL-12 is mediated, at least in part, by TNF-α.

scholarly journals iRhom2: An Emerging Adaptor Regulating Immunity and Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6570 ◽  
Author(s):  
Mazin A. Al-Salihi ◽  
Philipp A. Lang
Keyword(s):  
Critical Role ◽  
Growth Factor Receptor ◽  
Biologically Active ◽  
Necrosis Factor Alpha ◽  
Dna Viruses ◽  
Catalytic Center ◽  
Intramembrane Proteases ◽  
Epidermal Growth ◽  
Factor Alpha

The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFα), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling. Accordingly, with iRhom2 having a profound influence on ADAM17 activation and substrate specificity it regulates these signaling pathways. Moreover, iRhom2 has a role in the innate immune response to both RNA and DNA viruses and in regulation of keratin subtype expression in wound healing and cancer. Here we review the role of iRhom2 in immunity and disease, both dependent and independent of its regulation of ADAM17.

scholarly journals The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses

2008 ◽  
Vol 76 (8) ◽  
pp. 3717-3724 ◽  
Author(s):  
Jeffrey M. Jordan ◽  
Michael E. Woods ◽  
Juan Olano ◽  
David H. Walker
Keyword(s):  
Rickettsia Conorii ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tlr4 Signaling ◽  
Rickettsial Infections ◽  
Factor Alpha ◽  
Intravenous Inoculation

ABSTRACT The importance of toll-like receptor 4 (TLR4) in immunity to rickettsiae remains elusive. To investigate the role of TLR4 in protection against rickettsioses, we utilized C3H/HeJ mice, which are naturally defective in TLR4 signaling, and compared the responses of C3H/HeN and C3H/HeJ mice following intravenous inoculation with Rickettsia conorii. Mice genetically defective in TLR4 signaling developed overwhelming, fatal rickettsial infections when given an inoculum that was nonfatal for TLR4-competent mice. In addition, mice lacking the ability to signal through TLR4 had significantly greater rickettsial burdens in vivo. Moreover, we observed greater concentrations of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha, IL-12p40, IL-12p70, and IL-17 in the sera of mice with intact TLR4 function as well as significantly greater quantities of activated CD4+ and CD8+ T lymphocytes. Additionally, we also observed that Th17 cells were present only in TLR4-competent mice, suggesting an important role for TLR4 ligation in the activation of this subset. In agreement with these data, we also observed significantly greater percentages of immunosuppressive regulatory T cells in the spleen during infection in TLR4-defective mice. Together, these data demonstrate that, while rickettsiae do not contain endotoxic lipopolysaccharide, they nevertheless initiate TLR4-specific immune responses, and these responses are important in protection.

scholarly journals Intracellular Adhesion Molecule 1 Plays a Key Role in Acquired Immunity to Salmonellosis

2003 ◽  
Vol 71 (10) ◽  
pp. 5881-5891 ◽  
Author(s):  
Simon Clare ◽  
Robert Goldin ◽  
Christine Hale ◽  
Richard Aspinall ◽  
Cameron Simmons ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Critical Role ◽  
Interleukin 2 ◽  
Sublethal Dose ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Intracellular Adhesion Molecule ◽  
Serovar Typhimurium ◽  
Factor Alpha

ABSTRACT This study investigated the role of intracellular adhesion molecule 1 (ICAM-1) during Salmonella enterica serovar Typhimurium infection of mice. We show that ICAM-1 is expressed in and around granulomas on day 4 of infection in wild-type mice. However, when naive ICAM-1−/− mice were challenged with a sublethal dose of serovar Typhimurium, there were no detectable differences in systemic bacterial burden over the first 9 days of infection compared to wild-type control mice. When mice were immunized with the S. enterica serovar Typhimurium vaccine strain SL2361 and then challenged with the virulent S. enterica serovar Typhimurium strain C5, 100% of the ICAM-1−/− mice succumbed to infection, compared to 30% of wild-type mice. T-cell responses, as measured by activation via interleukin-2 production, as well as antibody responses were comparable in the ICAM-1−/− and wild-type mice. Following challenge, counts in organs were significantly higher in the ICAM-1−/− mice, and histological examination of organs showed pathological differences. Strain SL3261-immunized wild-type mice had cellular infiltrate and normal granuloma formation in the liver and spleen on days 5 and 10 after challenge with strain C5. ICAM-1−/− mice had a similar infiltrate on day 5, whereas on day 10 the infiltrate was more widespread and there were fewer macrophages associated with the granulomas. High circulating levels of tumor necrosis factor alpha and gamma interferon, as well as a high burden of strain C5 in the blood, accompanied the differences in histopathology. In this study we show that ICAM-1 plays a critical role during rechallenge of immunized mice with virulent S. enterica serovar Typhimurium.

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