CXCL12 is a constitutive and inflammatory chemokine in the intestinal immune system.
BACKGROUND
Inflammatory bowel disease (IBD) is characterized by increased lymphocytic infiltrate to the lamina propria (LP) and upregulation of inflammatory chemokines and receptors. CXCL12 is a constitutive chemokine involved in lung, brain, and joint inflammation. We hypothesized that CXCL12 and its receptor, CXCR4, would have a constitutive and inflammatory role in the gut.


METHODS
Intestinal epithelial cells (IECs) and T lymphocytes were isolated from intestinal mucosa of IBD and control patients undergoing bowel resection. Autologous T cells were isolated from peripheral blood (PB). CXCL12 and CXCR4 expression by IECs was assessed by polymerase chain reaction and immunohistochemistry, lymphocyte phenotype by flow cytometry, and migration by Transwells.


RESULTS
IECs expressed CXCL12 and expression was increased and more diffuse in IBD compared to normal crypts (ulcerative colitis [UC] > Crohn's disease [CD], inflamed > noninflamed). CXCR4 was expressed by IECs, LP T cells (LPTs), and PB T cells (PBTs), and CXCR4+ cells were increased in IBD LP in situ. PBTs and LPTs from all patients had a high and comparable migration toward CXCL12 (P < 0.0001 and P < 0.05 vs. medium, respectively). Migration toward IBD-IEC-derived supernatant was significantly higher compared to normal. Antibodies against CXCR4 and CXCL12 blocked migration.


CONCLUSIONS
CXCL12 is expressed by normal IECs and upregulated and differentially distributed in IBD IECs. CXCR4 is expressed by IECs and LPTs, and CXCR4+ cells are significantly increased in IBD LP. CXCL12 is chemotactic for both PBTs and LPTs. Thus, CXCL12 and CXCR4 have a constitutive and inflammatory role in the intestinal mucosa and their selective therapeutic manipulation may be considered in IBD management.
IBD Center, Department of Gastroenterology and Liver Diseases, Tel-Aviv University, Tel-Aviv, Israel. irisd@tasmc.health.gov.il
Iris
I
Dotan
Lael
L
Werner
Sharon
S
Vigodman
Sigal
S
Weiss
Eli
E
Brazowski
Nitsan
N
Maharshak
Ofer
O
Chen
Hagit
H
Tulchinsky
Zamir
Z
Halpern
Hanan
H
Guzner-Gur
D015153:Blotting, Western; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4