Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa.
Fractalkine is a unique chemokine that combines properties of both chemoattractants and adhesion molecules. Fractalkine mRNA expression has been observed in the intestine. However, the role of fractalkine in the healthy intestine and during inflammatory mucosal responses is not known. Studies were undertaken to determine the expression and function of fractalkine and the fractalkine receptor CX3CR1 in the human small intestinal mucosa. We identified intestinal epithelial cells as a novel source of fractalkine. The basal expression of fractalkine mRNA and protein in the intestinal epithelial cell line T-84 was under the control of the inflammatory mediator IL-1beta. Fractalkine was shed from intestinal epithelial cell surface upon stimulation with IL-1beta. Fractalkine localized with caveolin-1 in detergent-insoluble glycolipid-enriched membrane microdomains in T-84 cells. Cellular distribution of fractalkine was regulated during polarization of T-84 cells. A subpopulation of isolated human intestinal intraepithelial lymphocytes expressed the fractalkine receptor CX3CR1 and migrated specifically along fractalkine gradients after activation with IL-2. Immunohistochemistry demonstrated fractalkine expression in intestinal epithelial cells and endothelial cells in normal small intestine and in active Crohn's disease mucosa. Furthermore, fractalkine mRNA expression was significantly up-regulated in the intestine during active Crohn's disease. This study demonstrates that fractalkine-CX3CR1-mediated mechanism may direct lymphocyte chemoattraction and adhesion within the healthy and diseased human small intestinal mucosa.
Muehlhoefer
A
A
Gastrointestinal Unit, Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Saubermann
L J
LJ
Gu
X
X
Luedtke-Heckenkamp
K
K
Xavier
R
R
Blumberg
R S
RS
Podolsky
D K
DK
MacDermott
R P
RP
Reinecker
H C
HC
D000073883:CX3C Chemokine Receptor 1; D051242:Caveolin 1; D022461:Caveolins; D002460:Cell Line; D016764:Cell Polarity / Q000276:immunology; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism; D003902:Detergents; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000096:biosynthesis; D015728:Receptors, HIV / Q000096:biosynthesis; D012995:Solubility; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C495540:CAV1 protein, human; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; D003902:Detergents; D006017:Glycolipids; D007375:Interleukin-1; D008565:Membrane Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D015728:Receptors, HIV