title: Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages.
abstract: OBJECTIVE
  To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).
  
  
  METHODS
  We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.
  
  
  RESULTS
  Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.
  
  
  CONCLUSIONS
  PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ramming
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Weinkam
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Kittan
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JHW
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
mesh_terms: D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics*; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006086:Graft vs Host Disease / Q000150:complications; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000473:pathology*; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000235:genetics
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D015850:Interleukin-6; D058988:Phosphodiesterase 4 Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D001761:Bleomycin; D013792:Thalidomide; D003094:Collagen; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004264:DNA Topoisomerases, Type I; D020889:Rolipram; C505730:apremilast
keywords: Autoimmune Diseases; Fibroblasts; Systemic Sclerosis