Human secreted stabilin-1-interacting chitinase-like protein aggravates the inflammation associated with rheumatoid arthritis and is a potential macrophage inflammatory regulator in rodents.
Słowa kluczowe
Abstrakcyjny
OBJECTIVE
To study the relationship between the human secreted protein stabilin-1-interacting chitinase-like protein (SI-CLP) and rheumatoid arthritis (RA).
METHODS
The expression of SI-CLP in peripheral blood mononuclear cells (PBMCs) and synovial fluid from patients with RA and the effects of cytokines on SI-CLP expression were examined by Western blotting. Fluorescence-activated cell sorting analysis was performed to investigate the binding between SI-CLP and cells. Bone marrow-derived macrophages were isolated from wild-type and SI-CLP(-/-) mice, and real-time quantitative polymerase chain reaction was performed to detect the levels of messenger RNA for cytokines or SI-CLP in SI-CLP- or cytokine-treated macrophages. Histologic studies were conducted to evaluate inflammation and the expression of interleukin-12 (IL-12), IL-13, and SI-CLP in lesions. Enzyme-linked immunosorbent assays were used to detect the cytokine levels in bone marrow-derived macrophages. Rats or mice with collagen-induced arthritis (CIA) and SI-CLP(-/-) mice were used to study the function of SI-CLP in RA.
RESULTS
SI-CLP expression was increased in PBMCs and detectable in synovial fluid from patients with RA. Administration of SI-CLP to rats with CIA aggravated arthritis-associated inflammation. SI-CLP was specifically attached to the surface protein of macrophages, which elevated the expression of IL-1β, IL-6, IL-12, and IL-13 in macrophages and mouse bone marrow-derived macrophages, up-regulating ERK phosphorylation. Moreover, SI-CLP was up-regulated by both IL-12 and IL-13 through JNK and JAK/STAT signaling, respectively. Knockout of SI-CLP resulted in a decrease in the expression of IL-1β, IL-6, IL-12, and IL-13 and lower susceptibility to CIA compared with wild-type mice. SI-CLP treatment also aggravated arthritis-related inflammation in wild-type and SI-CLP(-/-) mice.
CONCLUSIONS
SI-CLP functions as a regulator of the inflammatory response by macrophages. The decrease in inflammation-associated cytokine levels resulting from SI-CLP knockout may explain the lower susceptibility to CIA in SI-CLP(-/-) mice.
