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.