The prostacyclin analogue treprostinil blocks NFkappaB nuclear translocation in human alveolar macrophages.
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 NFkappaB activation, but IkappaB-alpha phosphorylation and degradation are unaffected. Moreover, TRE does not affect the formation of the NFkappaB.DNA complex but blocks nuclear translocation of p65. These results are the first to illustrate the anti-cytokine actions of TRE in down-regulating NFkappaB, 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 NFkappaB may contribute to the efficacy of TRE therapy in PPH.
Raychaudhuri
Baisakhi
B
Department of Pulmonary and Critical Care Medicine, Anatomic Pathology, and Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195-5038, USA.
Malur
Anagha
A
Bonfield
Tracey L
TL
Abraham
Susamma
S
Schilz
Robert J
RJ
Farver
Carol F
CF
Kavuru
Mani S
MS
Arroliga
Alejandro C
AC
Thomassen
Mary Jane
MJ
D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D008264:Macrophages / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D013997:Time Factors; D051996:Transcription Factor RelA
D000959:Antihypertensive Agents; D016207:Cytokines; D015850:Interleukin-6; D007378:Interleukins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D011464:Epoprostenol; C427248:treprostinil