PMID- 26972571
OWN - NLM
STAT- MEDLINE
DCOM- 20170724
LR  - 20211204
IS  - 1365-2133 (Electronic)
IS  - 0007-0963 (Linking)
VI  - 175
IP  - 2
DP  - 2016 Aug
TI  - Microarray study reveals a transforming growth factor-beta-dependent mechanism of 
      fibrosis in discoid lupus erythematosus.
PG  - 302-13
LID - 10.1111/bjd.14539 [doi]
AB  - BACKGROUND: Discoid lupus erythematosus (DLE) is characterized by scarring 
      lesions that develop and perpetuate fibrotic lesions. These are not observed in 
      subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of 
      this is currently unknown. OBJECTIVES: To identify contradistinctive signalling 
      pathways and cellular signatures between the two type of lupus, with a focus on 
      the molecular mechanisms leading to fibrosis. METHODS: We conducted a gene 
      expression microarray analysis in lesional and nonlesional skin biopsy specimens 
      of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory 
      reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and 
      immunohistochemistry were performed on selected transcripts in a new cohort of 
      paraffin-embedded skin biopsies (n = 20). Changes over time of a group of 
      selected inflammatory and fibrotic genes were also evaluated in a second biopsy 
      taken 12 weeks later. In vitro functional studies were performed in primary 
      isolated fibroblasts. RESULTS: Compared with nonlesional skin, DLE samples 
      expressed a distinctive T-cell gene signature. DLE samples displayed a 
      significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine 
      predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and 
      immunochemical analysis over time showed a progressive increment of fibrotic 
      markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, 
      TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor 
      (TGF)-beta-dependent mechanism of fibrosis in DLE, also confirmed by the results 
      observed following in vitro stimulation with TGF-beta. CONCLUSIONS: These results 
      highlight major pathogenic pathways in DLE and provide novel molecular targets 
      for the development of new therapies. The data suggest the existence of a 
      TGF-beta-dependent pathway inducing fibrosis in DLE.
CI  - (c) 2016 British Association of Dermatologists.
FAU - Sole, C
AU  - Sole C
AD  - Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari 
      Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
FAU - Gimenez-Barcons, M
AU  - Gimenez-Barcons M
AD  - Department of Immunology, Hospital Universitari Vall d'Hebron, Universitat 
      Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
FAU - Ferrer, B
AU  - Ferrer B
AD  - Department of Pathology, Hospital Universitari Vall d'Hebron, Universitat 
      Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
FAU - Ordi-Ros, J
AU  - Ordi-Ros J
AD  - Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari 
      Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
FAU - Cortes-Hernandez, J
AU  - Cortes-Hernandez J
AD  - Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari 
      Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, 
      Barcelona, Spain.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20160529
PL  - England
TA  - Br J Dermatol
JT  - The British journal of dermatology
JID - 0004041
RN  - 0 (FOXP3 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Genetic Markers)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SERPINE1 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
RN  - EC 2.7.11.30 (TGFBR1 protein, human)
SB  - IM
MH  - Cells, Cultured
MH  - Fibroblasts/metabolism/physiology
MH  - Fibrosis/genetics
MH  - Forkhead Transcription Factors/metabolism
MH  - Gene Expression/genetics
MH  - Genetic Markers/genetics
MH  - Humans
MH  - Lupus Erythematosus, Cutaneous/*genetics/metabolism
MH  - Lupus Erythematosus, Discoid/*genetics/metabolism
MH  - Phosphorylation/physiology
MH  - Plasminogen Activator Inhibitor 1/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Receptor, Transforming Growth Factor-beta Type I
MH  - Receptors, Transforming Growth Factor beta/metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Signal Transduction/physiology
MH  - Skin/metabolism/*pathology
MH  - Smad3 Protein/metabolism
MH  - T-Lymphocytes, Helper-Inducer/metabolism/physiology
MH  - Tissue Array Analysis
MH  - Transforming Growth Factor beta1/genetics/pharmacology/*physiology
MH  - Up-Regulation/physiology
EDAT- 2016/03/15 06:00
MHDA- 2017/07/25 06:00
CRDT- 2016/03/15 06:00
PHST- 2016/02/08 00:00 [accepted]
PHST- 2016/03/15 06:00 [entrez]
PHST- 2016/03/15 06:00 [pubmed]
PHST- 2017/07/25 06:00 [medline]
AID - 10.1111/bjd.14539 [doi]
PST - ppublish
SO  - Br J Dermatol. 2016 Aug;175(2):302-13. doi: 10.1111/bjd.14539. Epub 2016 May 29.