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Parthenolide Inhibits IB Kinase, NF-B Activation, and Inflammatory Response in Cystic Fibrosis Cells and Mice

Department of Pediatrics, Rainbow Babies and Childrens' Hospital, Case Western Reserve University School of Medicine; and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Melvin Berger, M.D., Ph.D., Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: mxb12{at}po.cwru.edu

Cystic fibrosis (CF) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF-B. Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for anti-inflammatory activity. Several studies suggest that this compound inhibits the NF-B pathway, but the exact site is controversial. We hypothesized that parthenolide might ameliorate the excessive inflammatory response in CF models by inhibiting activation of NF-B. This was tested in vitro, using two pairs of cell lines with defective versus normal CF transmembrane conductance regulator (CFTR) (antisense/sense transfected 16 HBE and IB-3/S9), and in vivo, using CFTR-knockout (KO) mice. All cell lines were pretreated with parthenolide and then stimulated with IL-1 and/or TNF. Parthenolide significantly inhibited IL-8 secretion induced by these cytokines and prevented NF-B activation, IB degradation, and IB Kinase complex activity. CFTR-KO and wild-type mice were pretreated with parthenolide or vehicle alone then challenged intratracheally with LPS. Bronchoalveolar lavage was performed 3, 6, and 8 h later. Parthenolide pretreatment inhibited PMN influx as well as cytokine and chemokine production. This was also associated with inhibition of IB degradation and NF-B activation. We thus conclude that parthenolide inhibits IB kinase, resulting in stabilization of cytoplasmic IB, which in turn leads to inhibition of NF-B translocation and attenuation of subsequent inflammatory responses. IB kinase may be a good target, and parthenolide and/or feverfew might be promising treatments for the excessive inflammation in CF.

Key Words: cystic fibrosis • IB kinase • lung • NF-B • parthenolide

CLINICAL RELEVANCE Natural compounds such as parthenolide, which is a sesquiterpene lactone, have powerful anti-inflammatory properties, and might be used safely to inhibit the inflammatory processes that lead to lung destruction and death in patients with cystic fibrosis.

 

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