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Originally published In Press as doi:10.1074/jbc.M203567200 on June 24, 2002

J. Biol. Chem., Vol. 277, Issue 36, 33344-33348, September 6, 2002
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The Prostacyclin Analogue Treprostinil Blocks NFkappa B Nuclear Translocation in Human Alveolar Macrophages*

Baisakhi RaychaudhuriDagger , Anagha MalurDagger , Tracey L. BonfieldDagger , Susamma AbrahamDagger , Robert J. Schilz§, Carol F. FarverDagger §, Mani S. KavuruDagger , Alejandro C. ArroligaDagger , and Mary Jane ThomassenDagger §||

From the Departments of Dagger  Pulmonary and Critical Care Medicine, § Anatomic Pathology, and  Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195-5038

Primary pulmonary hypertension (PPH) is characterized by increased pulmonary arterial pressure and vascular resistance. We and others have observed that inflammatory cytokines and infiltrates are present in the lung tissue, but the significance is uncertain. Treprostinil (TRE), a prostacyclin analogue with extended half-life and chemical stability, has shown promise in the treatment of PPH. We hypothesize that TRE might exert beneficial effects in PPH by antagonizing inflammatory cytokine production in the lung. Here we show that TRE dose-dependently inhibits inflammatory cytokine (tumor necrosis factor-alpha , interleukin-1beta , interleukin-6, and granulocyte macrophage colony-stimulating factor) secretion and gene expression by human alveolar macrophages. TRE blocks NFkappa B activation, but Ikappa B-alpha phosphorylation and degradation are unaffected. Moreover, TRE does not affect the formation of the NFkappa B·DNA complex but blocks nuclear translocation of p65. These results are the first to illustrate the anti-cytokine actions of TRE in down-regulating NFkappa B, not through its inhibitory component or by direct binding but by blocking nuclear translocation. These data indicate that inflammatory mechanisms may be important in the pathogenesis of PPH and cytokine antagonism by blocking NFkappa B may contribute to the efficacy of TRE therapy in PPH.

* This work was supported in part by American Lung Association research Grant RG-027 (to B. R.) and National Institutes of Health Grant HL 67676 (to M. J. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Desk A90, 9500 Euclid Ave., Cleveland, Ohio 44195-5038. Tel.: 216-444-4429; Fax: 216-444-5172; E-mail: thomasm@ccf.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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