Anti-interferon-inducible chemokine, CXCL10, reduces colitis by impairing T helper-1 induction and recruitment in mice.
BACKGROUND
Colitis in interleukin (IL)-10 mice is a CD4 T helper 1 (TH1)-mediated disease characterized by intermittent, transmural inflammation reminiscent of human Crohn's disease. In this study, we investigated the hypothesis that production of the CXC chemokine CXCL10 (interferon [IFN]gamma-inducible protein 10) enhances induction of inflammatory responses in draining lymph nodes (LNs) and promotes colonic TH1 cell recruitment.


METHODS
Colitis was induced in B6 IL-10 mice. Mice were given anti-CXCL10 mAb in 2-week intervals before and after peak colitis. Colitis severity was graded and cytokine/chemokine levels were analyzed by real-time polymerase chain reaction. Cell yields were quantitated and effector cell recruitment was assessed by recovery of transferred D011.10 TH1 cells shortly (72 h) after transfer.


RESULTS
Treatment with anti-CXCL10 during colitis development decreased clinical and histologic disease severity as well as cytokine/chemokine mRNA and accumulation of mononuclear cells in LNs and colon. Treatment of mice with severe colitis reduced colitis scores and cell yields to lesser degrees. Anti-CXCL10 specifically decreased recruitment of transferred TH1 cells into mesenteric LNs (MLNs) and colon of IL-10 mice by 75% (P<0.05).


CONCLUSIONS
These results suggest that CXCL10 plays a dual role in colitis development by enhancing TH1 cell generation in inductive sites and promoting effector cell recruitment to inflamed tissue. Blockade of CXCL10 may be a useful adjunct to remission-inducing therapies in inflammatory bowel disease (IBD) by impairing disease recurrence through selective inhibition of effector cell generation and trafficking in vivo.
Hyun
Jae Geun
JG
Department of Internal Medicine, Division of Gastroenterology, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Lee
Goo
G
Brown
Jeffrey B
JB
Grimm
Gery R
GR
Tang
Yueming
Y
Mittal
Navhda
N
Dirisina
Ramanarao
R
Zhang
Zheng
Z
Fryer
Jonathan P
JP
Weinstock
Joel V
JV
Luster
Andrew D
AD
Barrett
Terrence A
TA
D000818:Animals; D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D003092:Colitis / Q000276:immunology*; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse