Human secreted stabilin-1-interacting chitinase-like protein aggravates the inflammation associated with rheumatoid arthritis and is a potential macrophage inflammatory regulator in rodents.
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.
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
Weichun
W
Xiao
Geng
G
Meng
Yanmei
Y
Zhao
Huihui
H
Yuan
Tingting
T
Li
Yanyan
Y
Peng
Yong
Y
Zhao
Ming
M
Luo
Wenming
W
Zhao
Zhanguo
Z
Li
Xiaofeng
X
Zheng
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000378:metabolism
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C510246:CHID1 protein, human; C000590738:Chid1 protein, Mouse; C000590739:SI-CLP protein, rat