Cholecystokinin octapeptide exerts its therapeutic effects on collagen-induced arthritis by suppressing both inflammatory and Th17 responses

Abstract

The purpose of this study was to evaluate the potential therapeutic effect of cholecystokinin octapeptide (CCK-8) on collagen-induced arthritis (CIA), an accepted murine experimental disease model with diverse histopathological features similar to human rheumatoid arthritis (RA). CIA was induced in DBA/1J mice by immunization with chicken collagen type II (CII). CCK-8 at different doses was intraperitoneally administered daily for 1 week. Mice treated with CCK-8 at doses of 5 and 10 nmol but not 1 nmol displayed much delayed onset of CIA and significantly lower incidence and decreased severity of arthritis. CCK-8 treatment significantly reduced the production of cytokines (IL-17, IL-23, IL-6 and TNF-α) and chemokines monocyte chemoattractant protein 1 in the joints of arthritic mice or in synovial cell culture supernatant, and increased the levels of IFN-γ and TGF-β. T cells from CCK-8 treated mice proliferated much less, produced low level of IL-17 and high levels of IFN-γ and TGF-β. Moreover, CCK-8 treated mice showed lower levels of CII-specific IgG, particularly that of IgG2a, in sera than those from control mice. These results indicate that CCK-8 is effective in suppressing both inflammatory and Th17 responses in CIA. CCK-8 may represent a new therapeutic modality for rheumatoid arthritis.

Cholecystokinin octapeptide (CCK-8): friend or foe for rheumatoid arthritis?

“…In this research, Li et al showed that CCK-8 treatment significantly reduced the production of cytokines (IL-17, IL-23, IL-6 and TNF-beta) and chemokines MCP-1 in the joints of arthritic mice or in synovial cell culture supernatant. Meanwhile, CCK-8 increased the levels of IFN-gamma and TGF-beta [1].…”

CCK8 negatively regulates the TLR9‐induced activation of human peripheral blood pDCs by targeting TRAF6 signaling

“…In recent years, a series of studies focused on the effect of CCK8 against endotoxin shock [13], rheumatoid arthritis [17], and inflammation [24] performed in our laboratory, have pointed to the involvement of CCK8 in the regulation of murine T cells, B cells and bone marrow-derived cDCs. The effects of CCK8 on human peripheral blood pDCs have so far not been investigated.…”

“…Our previous studies showed that treatment with the CCK8 (10 −8 mol/L) in vivo significantly suppressed the development of collagen-induced arthritis [17], a murine experimental rheumatoid arthritis model. With the emergence of elevated IFN levels as a pathogenic factor in several autoimmune diseases, the potentially important role of pDCs in autoimmunity has been recognized [4].…”

“…We found that CCK8 was a negative modulator of the DAG-PKC signaling pathway in resting rat pulmonary interstitial macrophages, playing important roles in maintaining body homeostasis, and inhibiting LPS-induced DAG content, PKC activity, and PKCζ translocation significantly in a dose-dependent manner through the CCK receptor [16]. Our previous studies showed that CCK8 could effectively inhibit the progression of collagen-induced arthritis [17], a murine experimental disease model, by attenuating inflammatory cell infiltration and reducing the production of proinflammatory cytokines (IL-17, IL-23, IL-6, and TNF-α) and the chemokine monocyte chemoattractant protein 1 in the joints of arthritic mice, and increasing production of the antiinflammatory cytokine TGF-β [18]. With the emergence of elevated IFN levels as a pathogenic factor in several autoimmune diseases, the potentially important role of pDCs in autoimmunity has been recognized [19,20].…”

Cholecystokinin octapeptide inhibits immunoglobulin G1 production of lipopolysaccharide-activated B cells

“…However, emerging evidence suggests that CCK-8 could exert immunomodulatory effects on macrophages, dendritic cells, T cells and B cells [1][2][3][4]. CCK-8 inhibits phenotypical and functional maturation, down-regulates B7.1 and B7.2 expressions of dendritic cells, inhibits co-stimulatory activity in lipopolysaccharide (LPS)-activated B cells, modulates Th1/Th2 imbalance, inhibits the production of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and increases the expression of anti-inflammatory cytokines, such as IL-4 in LPS-activated macrophages and B cells.…”