Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis.
BACKGROUND
Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models.


METHODS
Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice.


RESULTS
Proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-κB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice.


CONCLUSIONS
Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.
Yoshino
Takuya
T
Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nakase
Hiroshi
H
Honzawa
Yusuke
Y
Matsumura
Kayoko
K
Yamamoto
Shuuji
S
Takeda
Yasuhiro
Y
Ueno
Satoru
S
Uza
Norimitsu
N
Masuda
Satohiro
S
Inui
Kenichi
K
Chiba
Tsutomu
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000209:etiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000627:therapeutic use*
D016207:Cytokines; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D016753:Interleukin-10; D016264:Dextran Sulfate; D020928:Mitogen-Activated Protein Kinases; D016559:Tacrolimus