Suppression of cytokine-mediated β2-integrin activation on circulating neutrophils in critically ill patients

Rosenbloom, Alan J.; Pinsky, Michael R.; Napolitano, C; Nguyen, Thu‐Song; Levann, Douglas; Pencosky, Nicole; Dorrance, Adrienne M.; Ray, Barry K.; Whiteside, Theresa L.

doi:10.1002/jlb.66.1.83

Cited by 42 publications

(31 citation statements)

References 29 publications

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“…It is well known that several products of coagulation and fibrinolysis profoundly affect many facets of inflammatory reactions, such as induction of platelet activation (39), cytokine production by mononuclear phagocytes (40 -42), neutrophil aggregation, and chemotaxis (43- (9) recently reported selective activation of NF-B and AP-1 by physiological concentrations of soluble fibrinogen in PMA-differentiated U937 cells. Even more interesting, our results indicate that hFbg exerts its modulatory effect only on PMN previously primed by a purification procedure (34) or by TNF-␣ pretreatment (35). These results are in agreement with previous reports that show that ␤ 2 integrins are unable to interact with their physiological ligands in unstimulated leukocytes, a safety mechanism that controls acute and chronic inflammatory responses (6).…”

Section: Discussionsupporting

confidence: 92%

“…For activation parameters, we additionally demonstrate that hFbg induces the enhancement of CD11b and CD66b on the PMN surface. CD11b is up-regulated within minutes of exposure to proinflammatory substances such as TNF-␣, IL-8, C5a, leukotriene B 4 , and platelet-activating factor (35). However, like other integrins, CD11b must not only increase the expression on the cell, but it must undergo a qualitative change as well as bind to its counter-receptors (50).…”

Section: Discussionmentioning

confidence: 99%

“…To understand the biological meaning of such findings and taking into account that standard preparative techniques for PMN purification using a Ficoll-Hypaque gradient may result in neutrophil priming (34), we hypothesized that hFbg would not be able to mediate neutrophil activation until priming occurs. To test this possibility we performed ex vivo experiments conducted on whole blood as previously described (35). The primed status of purified neutrophils was confirmed by CD66b up-regulation (MFI (mean Ϯ SEM): PMN in whole blood, 147 Ϯ 12; after PMN purification, 284 Ϯ 45 ( p Ͻ 0.04); whole blood plus TNF-␣, 340 Ϯ 37 (not significant vs after PMN purification); n ϭ 6).…”

Section: Human Fbg Induces Full Activation Of Neutrophils After Primingmentioning

confidence: 99%

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Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Rubel

Fernández

Dran

et al. 2001

The Journal of Immunology

120

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The acute phase of the inflammatory response involves an increase in the concentrations of different plasma proteins that include fibrinogen (Fbg) and multiple proinflammatory mediators. In parallel, neutrophil activation is thought to play a crucial role in several inflammatory conditions, and it has been recently demonstrated that Fbg specifically binds to the α-subunit of CD11b/CD18 on neutrophil surface. Although several reports have shown that CD11b engagement modulates neutrophil responses, the effect of human Fbg (hFbg), one of CD11b physiologic ligands, has not been exhaustively investigated. We have now shown that incubation of purified neutrophils with hFbg induces a transient and rapid elevation of free intracellular Ca2+. This early intracellular signal is accompanied by changes in the expression of neutrophil activation markers, including enhancement of CD11b and CD66b, and down-regulation of FcγRIII. In addition, we have evaluated the effect of hFbg on two functional events related to expression and resolution of inflammation: cytotoxic capacity and rate of neutrophil apoptosis. We have found that activation of neutrophils by hFbg resulted in both enhancement of phagocytosis and Ab-dependent cellular cytotoxicity, and delay of apoptosis. We conclude that during inflammatory processes, soluble Fbg could influence neutrophil responses, increasing and prolonging their functional capacity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Human Fbg Induces Full Activation Of Neutrophils After Primingmentioning

confidence: 99%

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Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Rubel

Fernández

Dran

et al. 2001

The Journal of Immunology

120

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“…CD11b plays a central role in inflammation and in the systemic inflammatory response syndrome (18). Integrin belongs to a family of adhesion receptors and is found on the majority of cells in the body (19).…”

Section: Discussionmentioning

confidence: 99%

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Castellheim

Pharo

Fung³

et al. 2005

Pediatr Res

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Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconiuminduced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60 -70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response. Abbreviations ARDS, acute respiratory distress syndrome AU, arbitrary units DHR, dihydrorhodamine LPS, lipopolysaccharide MAS, meconium aspiration syndrome MFI, median fluorescence intensity PE, phycoerythrin PMA, phorbol-12-␤-myristat-13-␣-acetate TCC, terminal SC5b-9 complement complex Meconium aspiration syndrome (MAS) may cause a profound lung inflammation similar to acute respiratory distress syndrome (ARDS). A substantial increase in neutrophils in the airways; increased levels of inflammatory cytokines, eicosanoids, superoxide anions, and endothelin-1; expression of inducible nitric oxide synthase and cyclooxygenase-2; and activation of nuclear factor-B have been described in MAS (1-8). A profound inflammatory response and the release of leukocyte cytotoxic products have an important role in initiation and propagation of lung injury in ARDS, in which neutrophils and their cytotoxic products play a crucial role (9).The complement system is a key mediator of inflammation. Complement-mediated activation of neutrophils and monocytes leads to cytokine production; release of lipid mediators and histamine; oxidative burst; and altered expression of adhesion molecules, including increased expression of CD11b and shedding, revealed as decreased expression of CD62L. We showed recently that meconium is a potent activator of the alternative complement pathway in vitro (10). To study the interaction between all participating inflammatory systems, we used an in vitro human whole-blood model that is based on the use of lepirudin, a thrombin-specific anticoagulant that does not interfere with complement activation (11). We hypot...

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“…The downregulation of the CD11b response was present before and after TNF-· stimulation on lymphocytes, was present to a lesser extent on neutrophils, but was absent from monocytes, suggesting that different mechanisms of downregulation/control might exist for each cell type. The downregulation of CD11b expression on lymphocytes and neutrophils, when TNF-· is present in the serum, could offer a protective role against excess and damaging leucocyte activation, as can be seen in endotoxic shock [13] or in patients with systemic inflammatory response syndrome who have decreased CD11b activation on circulating leucocytes in response to TNF-· [14]. Conversely, an immune response which has been inappropriately 'damped down' may compromise host response and contribute to an increased risk of unrecognised and often fatal illness, often with a clinical scenario seen in very elderly subjects.…”

Section: Regression Analysis Of Tnf-· With Leucocyte Typementioning

confidence: 99%

Age-Related Alterations in Basal Expression and in vitro, Tumour Necrosis Factor Alpha Mediated, Upregulation of CD11b

et al. 2001

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Background: The β_2-integrin CD11b (Mac-1) plays a crucial role in the firm attachment of leucocytes to the endothelium during the inflammatory response. Objective: This study aimed to determine whether the increased incidence of infections witnessed in elderly individuals compared to their younger counterparts was associated with deficiencies in basal expression and/or upregulation of CD11b. Methods: Flow cytometry was used to measure CD11b expression, before and after in vitro tumour necrosis factor alpha (TNF-α) stimulation, on neutrophils, monocytes and lymphocytes from healthy volunteers aged less than 36 years and Senieur-approximated 70–85 and over 85 year olds. The TNF-α levels in serum were measured using a commercially available enzyme-linked immunoassay technique. Results: The basal expression of CD11b on monocytes and lymphocytes was highest in the 70–85-year-olds and lowest in the >85-year-olds. Following in vitro stimulation using low (10 IU) and high (100 IU) TNF-α concentrations, subjects >85 years consistently showed significantly lower increases in CD11b expression on each of the three cell types. The maximal increase in CD11b expression was in the 70–85-year age group for neutrophils and monocytes and in <36-year-olds for lymphocytes. Serum TNF-α was significantly higher in the elderly groups. Regression analysis showed a significant association between TNF-α and expression of CD11b on lymphocytes before and after TNF-α stimulation and for neutrophils before stimulation. Conclusions: The results of this study suggest that CD11b expression on leucocytes may not be consistent throughout life. Such age-related changes could compromise the inflammatory response, rendering individuals >85 years old more susceptible to infections. Alternatively, the lower levels of CD11b expression in this group may represent downregulation and protection against excess leucocyte activation within the vascular system and may, therefore, provide a mechanism for successful ageing.

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Suppression of cytokine-mediated β2-integrin activation on circulating neutrophils in critically ill patients

Cited by 42 publications

References 29 publications

Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Age-Related Alterations in Basal Expression and in vitro, Tumour Necrosis Factor Alpha Mediated, Upregulation of CD11b

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