A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concentrations: Oxidative stress-induced extracellular signal-regulated kinase activation without NF-kappa B inhibition

in Journal of Immunology (2002), 168(10), 5318-5325

An anti-inflammatory role and therapeutic potential for cyclopentenone PGs (cyPGs) has been suggested, based on observations that levels of cyPGs in exudates increase during the resolution phase of ... [more ▼]

An anti-inflammatory role and therapeutic potential for cyclopentenone PGs (cyPGs) has been suggested, based on observations that levels of cyPGs in exudates increase during the resolution phase of inflammation, and that exogenous cyPGs may attenuate the inflammatory response in vivo and in vitro mainly through inhibition of NF-kappaB, a critical activator of inflammatory gene expression. However, exogenous cyPGs inhibit NF-kappaB only at concentrations substantially higher than those of endogenous cyPGs present in inflammatory fluids, thus challenging the hypothesis that cyPGs are naturally occurring inhibitors of inflammation and suggesting that cyPGs at low concentrations might have previously unappreciated effects. In this study, using various cell types, we report that cyPGs, when used at concentrations substantially lower than required for NF-kappaB inhibition (viz, low micromolar concentrations), significantly potentiate the inflammatory response to TNF-alpha. At these concentrations, cyPGs induce production of reactive oxygen species, thereby synergizing with TNF-alpha to activate the extracellular signal-regulated kinase 1/2, an activation which in turn potentiates proinflammatory cytokine expression at both transcriptional and posttranscriptional levels. Our studs establishes a proinflammatory role for cyPGs at low micromolar concentrations, raises the possibility that cyPGs do not act as physiologic anti-inflammatory mediators, and questions the therapeutic potential of these compounds. [less ▲]

Nuclear factor-kB activity in human and animal models of inflammation : the case of asthma

Conference (2002)

NF-kB activity, and IL-8 and GM-CSF expression, in the milk of chorionic mastitis-affected cows

in National Mastitis Council Proceedings (2002)

Recent advances in bovine pneumology

in Kaske, Martin; Scholz, Henner; Höltershinken, Martin (Eds.) Recent developments and perspectives in bovine medicine (2002)

Modulation of dendritic cell phenotype by PGD2 and PGJ2 : consequence on the orientation of T helper response

in Proceedings : International Conference of the American Thoracic Society (2002)

CD40 engagement enhances eosinophil survival through induction of cellular inhibitor of apoptosis protein 2 expression: Possible involvement in allergic inflammation.

in Journal of Allergy and Clinical Immunology (The) (2002), 110(3), 443-9

BACKGROUND: CD40 engagement enhances eosinophil survival, suggesting a role for this receptor in the development of eosinophilia. OBJECTIVE: We examined whether CD40 enhances eosinophil survival by ... [more ▼]

BACKGROUND: CD40 engagement enhances eosinophil survival, suggesting a role for this receptor in the development of eosinophilia. OBJECTIVE: We examined whether CD40 enhances eosinophil survival by inducing the expression of antiapoptotic proteins. Three members of the inhibitor of apoptosis protein (IAP) family, namely cellular (c)-IAP1, c-IAP2, and XIAP, and 2 antiapoptotic proteins of the Bcl-2 family, namely Bcl-x(L) and Bfl-1/A1, were investigated. METHODS: Blood and sputum were obtained from healthy subjects and atopic asthmatic patients. Blood eosinophils were isolated by means of magnetic selection. Expression of CD40, IAPs, and Bcl-2 proteins was investigated by using flow cytometry, immunoblotting, or both. CD40 stimulation was achieved with agonistic antibodies or soluble ligands. Apoptosis was assessed by staining with propidium iodide and FITC-conjugated annexin-V. c-IAP2 expression was inhibited with antisense oligonucleotides. RESULTS: Freshly isolated eosinophils from healthy and asthmatic patients did not express CD40. Conversely, eosinophils expressed CD40 spontaneously when cultured for 48 hours. At this time point, CD40 stimulation significantly delayed eosinophil apoptosis. Inhibition of eosinophil apoptosis was accompanied by induction of c-IAP2 but not c-IAP1, XIAP, Bcl-x(L), or Bfl-1/A1 expression. Antisense knockdown of c-iap2 abolished CD40-induced enhancement of eosinophil survival. Sputum cells from asthmatic patients, unlike those from healthy subjects, substantially expressed CD40 and c-IAP2. Moreover, a strong correlation was found between the percentage of eosinophils in the sputum from asthmatic patients and the sputum level of CD40 and c-IAP2 expression. CONCLUSION: The results demonstrate that CD40 engagement enhances eosinophil survival through induction of c-IAP2 expression and suggest a role for this mechanism in allergic inflammation. [less ▲]

A pro-inflammatory role for the cyclopentenone prostaglandins at low concentrations: oxidative stress-induced ERK activation without NFKB inhibition

in Proceedings : Congress "Cell signaling, transcription and translation as therapeutics targets" (2002)

Local administration of nuclear factor-kB decoy oligodeoxinucleotides prevents allergic airway inflammation

in 12th European Respiratory Society Annual Congress (2002)

P65 Homodimer Activity in Distal Airway Cells Determines Lung Dysfunction in Equine Heaves

in Veterinary Immunology and Immunopathology (2001), 80(3-4), 315-26

Nuclear factor-kappaB (NF-kappaB) activity, which is a key regulator of inflammatory gene expression, is increased in bronchial epithelial cells from horses suffering from heaves (a hypersensitivity ... [more ▼]

Nuclear factor-kappaB (NF-kappaB) activity, which is a key regulator of inflammatory gene expression, is increased in bronchial epithelial cells from horses suffering from heaves (a hypersensitivity-associated inflammatory condition of the lung). To determine whether this increased activity extends to distal airways and to other pulmonary cells, cells recovered by broncho-alveolar lavage (BAL) in healthy and heaves-affected horses were assessed for NF-kappaB activity. NF-kappaB activity was much higher in BAL cells from heaves-affected horses, especially during crisis (disease exacerbation), than in cells from healthy horses. Moreover, the level of NF-kappaB activity found in BAL cells was positively correlated to total lung resistance and to the proportion of neutrophils present in BAL fluid. Finally, prototypical p65-p50 NF-kappaB heterodimers were absent from BAL cells, which mostly contained p65 homodimers. These results (1) show that increased NF-kappaB activity is a general feature of heaves lung; (2) demonstrate the importance of p65 homodimers in neutrophilic inflammation; and (3) suggest that the use of specific NF-kappaB inhibitors could improve lung function in heaves-affected horses. [less ▲]

Expression of c-inhibitor of apoptosis protein-2 in the sputum from asthmatic patients

in Proceedings : 11th European Respiratory Society Annual Congress, Eur. Respir. J., 2001, 18 (Suppl. 33) (2001)