Stimulatory effect of inflammatory cytokines on alpha 1-antichymotrypsin expression in human lung-derived epithelial cells.

Cichy, Joanna; Potempa, Jan; Chawla, Rajender K.; Travis, James

doi:10.1172/jci117975

Cited by 53 publications

(38 citation statements)

References 25 publications

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“…OSM was the most potent stimulator of ACT expression, not only in human astrocytes but also in the human astrocytoma cell lines U373 and CCF-STTG1 (data not shown). This finding correlates with the observation that OSM strongly activates ACT synthesis in bronchial epithelial cells (24). The OSM-or IL-1-induced ACT mRNA was very stable with a half-life of at least 12 h in human astrocytes (Fig.…”

Section: Osm Il-1 and Tnf-␣ Regulate The Expression Of Act Insupporting

confidence: 88%

Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate α1-Antichymotrypsin Expression in Human Cortical Astrocytes

Kordula¹,

Rydel²,

Brigham³

et al. 1998

Journal of Biological Chemistry

114

132

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␣ 1 -Antichymotrypsin (ACT) is an acute phase protein expressed in the brain which specifically colocalizes with amyloid-␤ during Alzheimer's disease. We analyzed ACT synthesis in cultured human cortical astrocytes in response to various cytokines and growth factors. Oncostatin M (OSM) and interleukin (IL)-1␤ were potent stimulators of ACT mRNA expression, whereas tumor necrosis factor-␣ had modest activity, and IL-6 and leukemia inhibitory factor (LIF) were ineffective. The finding that OSM, but not LIF or IL-6, stimulated ACT expression suggests that human astrocytes express a "specific" OSM receptor, but not IL-6 or LIF receptors. However, cotreatment of human astrocytes with soluble IL-6 receptor (sIL-6R)⅐IL-6 complex did result in potent stimulation of ACT expression. When the human ACT gene was cloned, two elements binding STAT1 and STAT3 (signal transducer and activator of transcription) in response to OSM or IL-6⅐sIL-6R complexes could be identified and characterized. Taken together, these findings indicate that OSM or IL-6⅐sIL-6 complexes may regulate ACT expression in human astrocytes and thus directly or indirectly contribute to the pathogenesis of Alzheimer's disease.1 is one of the major positive human acute phase proteins produced by the liver and secreted into blood plasma (1, 2). The expression of this proteinase inhibitor in hepatic cells is enhanced by interleukin (IL)-6 and glucocorticoids and to a lesser extent by IL-1 (3, 4). Although ACT is also found in the brain, the plasma-derived inhibitor is separated from this origin by a tight blood-brain barrier consisting of endothelial cells. For this reason it is believed that astrocytes are the likely source of ACT produced within the central nervous system (5). Significantly, ACT has been identified as one of the amyloid-associated proteins found in the brains of patients with Alzheimer's disease (6, 7). The pathological feature of this disease is cerebral degeneration with neuronal cell death and deposition of abnormal proteins in the form of amyloid plaques and neurofibrillary tangles. Because the expression of ACT is enhanced dramatically in affected brain regions in Alzheimer's disease, a state of cerebral "acute phase" in response to neuronal degradation has been proposed. IL-1 and IL-6, which are produced by cells of CNS, were suggested to induce ACT expression in astrocytes (8). Indeed, the induction of ACT expression by IL-1 has been shown in human astrocyte cultures (9); however, regulation by IL-6 has not been confirmed.To understand the control of ACT expression in the brain we used human astrocyte cultures and analyzed the pattern of its synthesis after stimulation with a variety of factors including IL-1 and cytokines of the IL-6 family. We have also cloned the 5Ј-flanking region of the ACT gene and performed analysis of its transcriptional activity. Our results suggest that at least one cytokine, oncostatin M (OSM), may play an important role in up-regulating ACT expression in astrocytes, whereas IL-6 requires the presence of solu...

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Section: Osm Il-1 and Tnf-␣ Regulate The Expression Of Act Insupporting

confidence: 88%

Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate α1-Antichymotrypsin Expression in Human Cortical Astrocytes

Kordula¹,

Rydel²,

Brigham³

et al. 1998

Journal of Biological Chemistry

114

132

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“…Despite evidence that ␣ 1 -antichymotrypsin can inhibit several proteinases in vitro and that it is selectively concentrated and synthesized in the lung (48), its physiological role remains unclear. The removal of ␣ 1 -antichymotrypsin from bronchoalveolar lavage had little effect on the total inhibitory capacity, suggesting that the majority of lung ␣ 1 -antichymotrypsin is inactive as a proteinase inhibitor (22).…”

Section: Resultsmentioning

confidence: 99%

Latent α1-Antichymotrypsin

Chang

Lomas

1998

Journal of Biological Chemistry

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␣ 1 -Antichymotrypsin is an acute phase protein that protects the tissues from damage by proteolytic enzymes, but previous studies have shown that ␣ 1 -antichymotrypsin within the lungs of patients with chronic bronchitis and emphysema is intact but inactive as an inhibitor. Ammonium sulfate fractionation followed by blue Sepharose and DNA-Sepharose chromatography was used to isolate small amounts of intact, monomeric but inactive ␣ 1 -antichymotrypsin from the plasma of 30 healthy blood donors. This species had a higher DNA binding affinity with more anodal electrophoretic mobility than native ␣ 1 -antichymotrypsin and was conformationally stable against thermal denaturation, 8 M urea, and 7 M guanidinium chloride. The protein was unable to accept synthetic reactive loop peptides, and the reactive loop was resistant to proteolytic cleavage at the P 5 -P 4 bond but could be cleaved between P 1 and P 3 . These data suggest that this new ␣ 1 -antichymotrypsin species was in a conformation similar to those of the crystallographically determined latent serpins, plasminogen activator inhibitor-1 and antithrombin. ␣ 1 -Antichymotrypsin from lung lavage migrated with the same electrophoretic mobility as the putative latent ␣ 1 -antichymotrypsin, suggesting that this is the inactive conformation described previously in the lungs of patients with chronic bronchitis and emphysema. This conformational transition of ␣ 1 -antichymotrypsin, from an active to an inactive state, within the lung may play an important role in the pathogenesis of chronic lung disease.

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“…At early stages of acute inflammation, the protease-antiprotease balance likely shifts in favor of proteolysis. However, as the inflammatory response continues, the plasma concentration of protease inhibitors increases (30,31). Therefore, at later stages of the inflammatory response or during ongoing inflammation, host proteases are neutralized by plasma inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

Kulig¹,

Zabel

Dubin

et al. 2007

The Journal of Immunology

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Chemerin is an attractant for cells that express the serpentine receptor CMKLR1, which include immature plasmacytoid dendritic cells (pDC) and macrophages. Chemerin circulates in the blood where it exhibits low biological activity, but upon proteolytic cleavage of its C terminus, it is converted to a potent chemoattractant. Enzymes that contribute to this conversion include host serine proteases of the coagulation, fibrinolytic, and inflammatory cascades, and it has been postulated that recruitment of pDC and macrophages by chemerin may serve to balance local tissue immune and inflammatory responses. In this work, we describe a potent, pathogen-derived proteolytic activity capable of chemerin activation. This activity is mediated by staphopain B (SspB), a cysteine protease secreted by Staphylococcus aureus. Chemerin activation is triggered by growth medium of clinical isolates of SspB-positive S. aureus, but not by that of a SspBnull mutant. C-terminal processing by SspB generates a chemerin isoform identical with the active endogenous attractant isolated from human ascites fluid. Interestingly, SspB is a potent trigger of chemerin even in the presence of plasma inhibitors. SspB may help direct the recruitment of specialized host cells, including immunoregulatory pDC and/or macrophages, contributing to the ability of S. aureus to elicit and maintain a chronic inflammatory state.

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Stimulatory effect of inflammatory cytokines on alpha 1-antichymotrypsin expression in human lung-derived epithelial cells.

Cited by 53 publications

References 25 publications

Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate α1-Antichymotrypsin Expression in Human Cortical Astrocytes

Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate α1-Antichymotrypsin Expression in Human Cortical Astrocytes

Latent α1-Antichymotrypsin

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

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