Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…+ T cells in a manner that does not exhibit elevation of IFN-g [21,222] and that IL-17 is linked to the inflammation seen in CIA and EAE [20,21,72]. Further evidence that IL-17 was derived in mice from a discrete population of Th cells that were distinct from the Th1 lineage, termed Th17 cells, were provided by publications showing resistance of Th1 and Th2 cells in vitro to proliferation or production of IL-17 following stimulation with IL-23 and that development of IL-17-producing cells was inhibited by the presence of IFN-g and/or IL-4 in the culture supernatant [223,224].…”

IL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?

“…Mouse studies IL-17 expression Spontaneously produced by RA synovium/synovial fluid [2,12] Locally in synovium of arthritic mice [8,11] IL-17 in inflammation IL-17 stimulates IL-6 and IL-8 in fibroblast, endothelial and epithelial cells [5,6] IL-17 induces synovial pro-inflammatory cytokines and chemokines such as TNF, IL-1, IL-6, RANKL, KC, LIX [11,33] IL-17 stimulates TNF, IL-1 in macrophages [7] IL-17 stimulates GM-CSF, PGE2 in synoviocytes [6] Strong inducer of neutrophil recruitment through chemokine release [8,9,33,78] IL-17 in early arthritis Distinct but transient synovial fluid cytokine profile, including IL-17 [3] Lack of IL-17 activity prevents development of CIA [8,[22][23][24] and prevents spontaneous development of arthritis [ [20] IFN-c protective [20] IL-17 and interplay with TNF and IL-1…”

“…Enhances IL-1 mediated IL-6 in RA synoviocytes as well as TNF-induced synthesis of IL-1, IL-6, IL-8 [15,16] IL-17 additative/synergistic effect with TNF or IL-1 [33] IL-17 synergize with IL-1, TNF [10,20,32] IL-17 effect is TNF dependent under naïve conditions, but TNF independent under arthritis conditions [38] IL-17 effect is IL-1 independent in experimental arthritis [8,37] IL-17 in bone damage IL-17 induces RANKL in cultures of osteoblasts [13] IL-17 induces bone damage in naïve mice, aggravates bone erosion in CIA [44] Synergy between IL-17 and TNF [20,25,32] IL-17-induced bone erosion is RANKL mediated [44] IL-17 in cartilage damage IL-17 induces NO [34], metalloproteinases in synoviocytes and chondrocytes [17][18][19] Inducer of NO and MMPs and inhibition of PG synthesis [26], aggravates cartilage erosion in CIA [8,9] Synergy between IL-17 and TNF [29] IL-1 independent role of IL-17 in cartilage damage [8,19,28] Th17 IL-17-producing cells in the synovium of RA patients (Th0/Th1 but not Th2) [14] IL-17-producing cells and Th17 in CIA and AIA arthritis models [55,60,70] effects of IL-17 on matrix degradation and synthesis were not dependent on IL-1 production by chondrocytes and IL-1Ra did not block IL-17-induced matrix release nor prevented inhibition of matrix synthesis in vitro using porcine articular cartilage explants [28]. On the other hand, the IL-17 induced production of prostaglandin E2 (PGE2) and nitric oxide (NO) by cartilage explants is LIF-dependent [28,36].…”

“…Early neutralization of IL-17 using sIL-17R:Fc fusion protein given systemically starting before arthritis expression in experimental arthritis prevented bone erosion [8,23]. On the other hand, local IL-17 overexpression in the knee joint of type II collagen-immunized mice results in promotion of collagen arthritis and aggravates joint destruction [9]. In the collagen-induced arthritis model it was shown that IL-17 promoted bone erosion through loss of the RANKL/OPG balance [44].…”

“…IL-17A can synergize with these cytokines (IL-1, TNF, RANKL), but has direct activity as well. Furthermore IL-17A is able to promote cartilage destruction and bone erosion in experimental arthritis [8,9]. When IL-17A is combined with other cytokines, already thought to be important in arthritic disease, even more marked tissue destruction occurs (10, Lubberts unpublished observations).…”