Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity.
Human intestinal epithelial cells secrete an array of chemokines known to signal the trafficking of neutrophils and monocytes important in innate mucosal immunity. We hypothesized that intestinal epithelium may also have the capacity to play a role in signaling host adaptive immunity. The CC chemokine macrophage inflammatory protein (MIP)-3alpha/CCL20 is chemotactic for immature dendritic cells and CD45RO(+) T cells that are important components of the host adaptive immune system. In these studies, we demonstrate the widespread production and regulated expression of MIP-3alpha by human intestinal epithelium. Several intestinal epithelial cell lines were shown to constitutively express MIP-3alpha mRNA. Moreover, MIP-3alpha mRNA expression and protein production were upregulated by stimulation of intestinal epithelial cells with the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-1alpha or in response to infection with the enteric bacterial pathogens Salmonella or enteroinvasive Escherichia coli. In addition, MIP-3alpha was shown to function as a nuclear factor-kappaB target gene. In vitro findings were paralleled in vivo by increased expression of MIP-3alpha in the epithelium of cytokine-stimulated or bacteria-infected human intestinal xenografts and in the epithelium of inflamed human colon. Mucosal T cells, other mucosal mononuclear cells, and intestinal epithelial cells expressed CCR6, the cognate receptor for MIP-3alpha. The constitutive and regulated expression of MIP-3alpha by human intestinal epithelium is consistent with a role for epithelial cell-produced MIP-3alpha in modulating mucosal adaptive immune responses.
Laboratory of Mucosal Immunology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623, USA.
A
A
Izadpanah
M B
MB
Dwinell
L
L
Eckmann
N M
NM
Varki
M F
MF
Kagnoff
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D054418:Chemokine CCL20; D019742:Chemokines, CC; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D016332:Fetal Tissue Transplantation; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007202:Indicators and Reagents; D007375:Interleukin-1 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology; D012480:Salmonella Infections / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D007202:Indicators and Reagents; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D012097:Repressor Proteins