Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis.
OBJECTIVE
This study was conducted to determine the expression pattern, regulation and function of CCL28 and CCR10 in rheumatoid arthritis (RA) pathogenesis.


METHODS
Expression of CCL28 and CCR10 was assessed in RA compared with other arthritis synovial tissues (STs) or fluids (SFs) by histology or ELISA. The factors modulating CCL28 and CCR10 expression were identified in RA myeloid and endothelial cells by ELISA, FACS and Western blotting. The mechanism by which CCL28 ligation promotes RA angiogenesis was examined in control and CCR10-knockdown endothelial cell chemotaxis and capillary formation.


RESULTS
CCL28 and/or CCR10 expression levels were accentuated in STs and SFs of patients with joint disease compared with normal controls and they were predominately coexpressed in RA myeloid and endothelial cells. We show that protein expression of CCL28 and CCR10 was modulated by tumour necrosis factor (TNF)-α and toll-like receptor 4 ligation in RA monocytes and endothelial cells and by interleukin (IL)-6 stimulation in RA macrophages. Neutralisation of CCL28 in RA SF or blockade of CCR10 on human endothelial progenitor cells (EPCs) significantly reduced SF-induced endothelial migration and capillary formation, demonstrating that ligation of joint CCL28 to endothelial CCR10+ cells is involved in RA angiogenesis. We discovered that angiogenesis driven by ligation of CCL28 to CCR10 is linked to the extracellular signal regulated kinase (ERK) cascade, as CCR10-knockdown cells exhibit dysfunctional CCL28-induced ERK signalling, chemotaxis and capillary formation.


CONCLUSIONS
The overexpression of CCL28 and CCR10 in RA ST and their contribution to EPC migration into RA joints support the CCL28/CCR10 cascade as a potential therapeutic target for RA.
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Zhenlong
Z
Chen
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Seung-Jae
SJ
Kim
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Abdul B
AB
Essani
Department of Microbiology & Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, Illinois, USA.
Michael V
MV
Volin
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Olga M
OM
Vila
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
William
W
Swedler
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Shiva
S
Arami
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Suncica
S
Volkov
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Latriese V
LV
Sardin
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Nadera
N
Sweiss
Division of Rheumatology, Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Shiva
S
Shahrara
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D020868:Gene Silencing; D006801:Humans; D007596:Joints / Q000098:blood supply; D020935:MAP Kinase Signaling System / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D054447:Receptors, CCR10 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology
C414047:CCL28 protein, human; C515706:CCR10 protein, human; D019742:Chemokines, CC; D012333:RNA, Messenger; D054447:Receptors, CCR10
Chemokines; Inflammation; Rheumatoid Arthritis; Synovial fluid; TNF-alpha