title: The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis.
abstract: Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R(+) monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti-IL-7 Ab or IgG control. Anti-IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti-IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Chen
authors.forename: Seung-jae
authors.initials: SJ
authors.lastname: Kim
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Chamberlain
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Pickens
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.forename: Suncica
authors.initials: S
authors.lastname: Volkov
authors.forename: Shiva
authors.initials: S
authors.lastname: Arami
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.forename: William
authors.initials: W
authors.lastname: Swedler
authors.forename: Anjali
authors.initials: A
authors.lastname: Mehta
authors.forename: Nadera
authors.initials: N
authors.lastname: Sweiss
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D000328:Adult; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D054426:Chemokine CXCL2; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells; D010010:Osteoclasts / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D013582:Synovial Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000906:Antibodies; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases