Submitted on December 10, 2007
Revised on January 8, 2009
Accepted on March 2, 2009
The PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-
1 stimulated fibroblasts
Shinsaku Togo1, Xiangde Liu2, Xingqi Wang2, Hisatoshi Sugiura3, Koichiro Kamio4, Shin Kawasaki5, Tetsu Kobayashi6, Ronald F. Ertl2, Youngsoo Ahn2, Olaf Holz7, Helgo Magnussen7, Karin Fredriksson8, C. Magnus Skold8, and Stephen I. Rennard9*
1 Juntendo Urayasu Hospital
2 University of Nebraska Medical Center
3 Wakayama Medical University
4 Nippon Medical School
5 Tokyo University Hospital
6 Mie University Graduate School of Medicine
7 Hospital Grosshansdorf
8 Karolinska Institutet
9 Univ of Nebraska Medical Center
* To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.
Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase 4 (PDE4) inhibitors, by preventing the breakdown of cyclic AMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. TGF-
1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE2 metabolism. The current study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was approximately 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-1 (0.05 < p <0.08). The effect of the PDE4 inhibitors was mediated through cyclic AMP stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also observed. The effect of PDE4 inhibitors depended on fibroblast production of PGE2, and TGF-1 induced PGE2 production. PDE4 inhibitors together with TGF-1 resulted in augmented PGE2 production together with increased expression of COX mRNA and protein. Taken together, the current study supports the concept that PDE4 inhibitors may attenuate fibroblast activities that can lead to fibrosis and that PDE4 inhibitors may be particularly effective in the presence of TGF-1 induced fibroblast stimulation.
