Functional implications of the IL-6 signaling pathway in keloid pathogenesis.
The molecular mechanism(s) behind keloid pathogenesis remains unclear. Previously by global gene expression analysis of keloid fibroblasts (KFs), we implicated the IL-6 signaling pathway in keloid pathogenesis. Here, we determine a functional role of IL-6 signaling in keloid scars. Primary cultures of KFs and surrounding nonlesional fibroblasts (NFs) were subjected to induction or inhibition of IL-6 or its specific receptor IL-6 receptor alpha (IL-6R alpha) and detection of their effects on extracellular matrix gene expression. The levels of gp130 and several downstream targets in IL-6 signaling were also examined. IL-6 secretion was significantly higher in KFs than NFs. Addition of IL-6 peptide to NFs culture or inhibition of IL-6 or its receptor IL-6R alpha by their corresponding antibodies in KFs culture revealed a dose-dependent increase or decrease in collagen type I alpha 2 and fibronectin 1 mRNAs, respectively. Induction of IL-6 by IL-1beta peptide and stimulation by IL-6 peptide in NFs, or inhibition of IL-6 or IL-6R alpha in KFs cultures demonstrated a dose-dependent increase or decrease in procollagen I synthesis, respectively. The mRNA and protein expressions of gp130 and several downstream targets in IL-6 signaling (JAK1, STAT3, RAF1, and ELK1) were upregulated in KFs versus NFs. Our results indicate that IL-6 signaling may play an integral role in keloid pathogenesis and provide clues for development of IL-6 receptor blocking strategies for therapy or prophylaxis of keloid scars.
Ghazizadeh
Mohammad
M
Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan. ciem@nms.ac.jp
Tosa
Mamiko
M
Shimizu
Hajime
H
Hyakusoku
Hiko
H
Kawanami
Oichi
O
D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007627:Keloid / Q000188:drug therapy / Q000209:etiology*; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003094:Collagen; D019908:Proto-Oncogene Proteins c-raf