Detection of Lipocortin 1 in Human Lung Lavage Fluid: Lipocortin Degradation As a Possible Proteolytic Mechanism in the Control of Inflammatory Mediators and Inflammation

Smith, Susan; Tetley, Teresa D.; Guz, A.; Flower, Roderick J.

doi:10.2307/3430676

Cited by 66 publications

(30 citation statements)

References 20 publications

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“…However, immunoblotting PBMC cellular protein or extracellular medium revealed in addition to LC-1, an immunoreactive species which was 7 kDa lighter (Figure 4a, b). Immunoblotting experiments by others have identified lower molecular mass species with LC-1 like immunoreactivity in the subcellular fractions from leukocytes (Smith et al, 1990;Peers et al, 1993). Findings of previous studies suggest that these LC-1-like proteins are the products of proteolytic degradation of full sequence LC-1 (Flower, 1988).…”

Section: Discussionmentioning

confidence: 96%

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

Sudlow

Carey

Forder

et al. 1996

British J Pharmacology

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Lipocortin‐1 and its N‐terminal derivatives exert potent inhibitory actions in various models of acute inflammation. The present study examined the ability of lipocortin (LC)‐1 to suppress the release of the acute pro‐inflammatory mediators, tumour necrosis factor (TNFα) and prostaglandin E2 (PGE2) from human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) or recombinant human interleukin‐1β (rhIL‐1β). LPS (10 μg ml−1)‐stimulated release of TNFα and PGE2 from PBMC was significantly inhibited by (4 h) co‐incubation of the cells with 10−6 m dexamethasone (Dex), but not with 10−9 m to 10−7 m of a N‐terminal fragment (amino acids 1–188) of recombinant human LC‐1 (LC‐1 fragment). However, Dex suppression of LPS‐stimulated TNFα and PGE2 secretion from PBMC was reversed when polyclonal antibody to LC‐1 fragment (1:10,000 dilution) was included in the medium. rhIL‐1β (5times10−8 m)‐stimulated release of TNFα and PGE2 from PBMC (after 18 h) was abolished by co‐incubation of the cells with 10−7 m LC‐1 fragment. After incubation with Dex (4 h), cellular proteins from PBMC were immunoblotted using anti‐LC‐1 fragment antibody (which showed no cross‐reactivity with human annexins 2 to 6). Dex caused no increase in immunoreactive (ir)LC‐1 content of PBMC, although there was a three fold increase in the amount of a lower mass species with LC‐1‐like immunoreactivity. This was accompanied by the appearance of irLC‐1 in the extracellular medium. The results of the present study implicate endogenous LC‐1 in glucocorticoid suppression of TNFα and PGE2 release from human PBMC and suggest an extracellular site of action for LC‐1. LC‐1 may also inhibit rhIL‐1β‐stimulated TNFα and PGE2 secretion from PBMC.

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Section: Discussionmentioning

confidence: 96%

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

Sudlow

Carey

Forder

et al. 1996

British J Pharmacology

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“…Other aspects of host defence were also explored in the current study, namely the direct anti-microbial actions of AnxA1 and its N-terminal truncated peptides. The N-terminus of AnxA1 is reported to contain cleavage sites for elastase (Smith et al 1990) and proteinase 3 enzymes which cleave at valine and alanine residues (Vong et al, 2007). The data indicates that the majority of the imunoreactive AnxA1 protein detected in human saliva samples is in the truncated form (~33kD).…”

Section: (Insert Figure 2 Around Here) Discussionmentioning

confidence: 98%

“…Oral epithelial cells, including cells of the buccal mucosa, tongue, small salivary glands as well as the parotid and submandibular salivary glands in humans (Dreier et al, 1998) also express AnxA1. This protein is also present in human mucosal secretions such as bronchoalveolar lavage fluid (Smith et al 1990) and more recently been detected in human saliva (Lorenz et al, 2011;Jarai et al, 2012).…”

Section: Introductionmentioning

confidence: 91%

Annexin-A1 protein and its relationship to cortisol in human saliva

Fowkes

Moradi-Bidhendi

Branceleone

et al. 2013

Psychoneuroendocrinology

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Abstract/SummarySalivary cortisol is commonly used as a clinical biomarker of endocrine status and also as a marker of psychosocial stress. Annexin-A1 (AnxA1) is an anti-inflammatory protein whose expression is modulated by glucocorticoids. Our principal objectives were to (i) detect the presence of and (ii) measure AnxA1 protein in whole human saliva and to (iii) investigate whether salivary cortisol and AnxA1 are correlated in healthy humans. A total of 37 healthy participants (male and female) were used in the study. Saliva was collected using salivette tubes. Salivary cortisol and AnxA1 protein were sampled at between 3 and 6 time points over 24 hours and measured for cortisol and AnxA1 protein using specific ELISA's. The presence of salivary AnxA1 protein was confirmed by western blotting.AnxA1 protein is detectable in whole human saliva, as detected by western blot analysis and ELISA. A diurnal rhythm was evident in both salivary cortisol (P < 0.01) and AnxA1 (P < 0.01) and was defined as a significant difference in time 0 (waking) samples compared to 'bed' (23.00 hrs) samples. AnxA1 protein did not exhibit an awakening response (P > 0.05), whereas salivary cortisol was significantly elevated between time 0 and 30 minutes post waking (P < 0.001).AnxA1 protein correlates positively with salivary cortisol, indicating that cortisol is most likely a regulator of AnxA1 in human saliva.

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“…After 1 h, the conditioned medium and any non-adherent cells were removed and cells and medium separated by centrifugation [10]. The acellular conditioned media were stored at -20°C until analysis.…”

Section: Bronchoalveolar Lavage Cell Culturementioning

confidence: 99%

“…Concentrates were Western blotted [10] and stained for ~t-l-proteinase inhibitor with a specific polyclonal antibody (DAKO, UK).…”

Section: Investigation Of Elastase: Ct-l-proteinase Inhibitor Mixturementioning

confidence: 99%

Compromised inhibition of human lung lavage cell elastases

et al. 1996

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Increased elastinolytic activity has been correlated with the degree of lung damage occurring in a variety of lung diseases including cystic fibrosis; serine proteinase inhibitors are currently on trial for the treatment of some lung disorders. ttowever, human lung lavage cells also secrete metallo-dependent elastases. Here we show, for the first time, that whilst these are readily inhibited by EDTA, inhibition of serine elastases using serpins (serine proteinase inhibitors) is not always possible. This may reflect inactivation of serpins by uninhibited metalloproteinases and oxidants in a low protein milieu. Thus, the therapeutic inhibition of excessive elastinolytic activity may require a combination of inhibitors to work efficiently. ~. IntroductionAn increase in the proteolytic activity of respiratory tract ~ecretions, in particular an excess of elastinolytic activity, has been implicated in the pathology of a number of pulmonary ,onditions including cystic fibrosis and acute lung injury, as well as in diseases of tobacco smokers such as bronchitis and ~mphysema [1][2][3][4][5].Elastinolytic enzymes are released by the polymorphonucear neutrophil, which produces at least two serine-dependent ~lastases, neutrophil elastase (EC 3.4.21.37) and proteinase 3 EC 3.4.21.76), and the alveolar macrophage which can ,ynthesize cysteinyl-and metalloenzymes with elastinolytic acivity (reviewed in [6]). The first elastinolytic enzyme to be dentified was neutrophil elastase, an enzyme with a broad ,pectrum of pro-inflammatory activity; in addition to its elasinolytic properties, it can act as a secretagogue, stimulate GM-CSF release from alveolar macrophages and act as a aeutrophil chemoattractant by activating C5a and stimulating IL-8 production by epithelial cells. Recently, attention has bcused on the matrix metalloproteinases (MMPs). Alveolar nacrophages constitutively produce MMPs-2, 3, 9, 10 and 12 md, thus, can degrade a variety of connective tissue compoaents, including elastin.The relative importance of the extracellular release of these iifferent classes of enzyme into the airspaces is unclear since ':hey have differing activities on a molar basis epithelial secretions contain inhibitors for all three classes of enzyme. Furthermore, the enzymes of one class may inactivate the inhibitors and activate the proenzymes of another class; either action could potentially amplify the elastinolytic burden of the lung. For example, neutrophil elastase can both activate metalloelastase (MMP-12; EC 3.4.24) and cleave its inhibitors; conversely, MMP-12 can inactivate at least one serine proteinase inhibitor (or serpin), ct-l-proteinase inhibitor [7]. As alveolar macrophages and neutrophils are often found in close proximity in the respiratory tract, particularly in pathological states, for example cystic fibrosis, such interactions may amplify the total elastase burden, so increasing the severity of tissue damage.To evaluate the elastinolytic potential of proteases released by mixed populations of bronchoalveolar lav...

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Detection of Lipocortin 1 in Human Lung Lavage Fluid: Lipocortin Degradation As a Possible Proteolytic Mechanism in the Control of Inflammatory Mediators and Inflammation

Cited by 66 publications

References 20 publications

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

Annexin-A1 protein and its relationship to cortisol in human saliva

Compromised inhibition of human lung lavage cell elastases

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Detection of Lipocortin 1 in Human Lung Lavage Fluid: Lipocortin Degradation As a Possible Proteolytic Mechanism in the Control of Inflammatory Mediators and Inflammation

Cited by 66 publications

References 20 publications

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE2 and TNFα release from human peripheral blood mononuclear cells

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE2 and TNFα release from human peripheral blood mononuclear cells

Annexin-A1 protein and its relationship to cortisol in human saliva

Compromised inhibition of human lung lavage cell elastases

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The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells