The IκB kinase inhibitor ACHP strongly attenuates TGFβ1-induced myofibroblast formation and collagen synthesis.
Excessive accumulation of a collagen-rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF-κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF-κB pathway. It is not known whether ACHP has potential anti-fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1-induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha-smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post-treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen-modifying enzymes lysyl hydroxylase (PLOD1, PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF-κB pathway plays an important role in myofibroblast biology.
Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Masum M
MM
Mia
Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Ruud A
RA
Bank
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D051785:Smad Proteins / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
C501280:2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile; C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D005353:Fibronectins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009539:Nicotinic Acids; D009570:Nitriles; C498143:RELA protein, human; D051785:Smad Proteins; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; C051615:transgelin; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D051550:I-kappa B Kinase
collagen; fibronectin; fibrosis; lysyl hydroxylase; myofibroblasts