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Production of MDC/CCL22 by human intestinal epithelial cells
M C Berin1, M B Dwinell, L Eckmann
1Laboratory of Mucosal Immunology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Insights
Intestinal epithelial cells produce Macrophage-derived chemokine (MDC/CCL22), attracting Th2 cytokine-producing T cells. This chemokine
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- The intestinal mucosa harbors Th2 cytokine-producing lymphocytes, but their recruitment signals are unclear.
- Macrophage-derived chemokine (MDC/CCL22) is a CC chemokine attracting Th2 cells expressing CCR4.
Purpose of the Study:
- To investigate the production and regulation of MDC/CCL22 by intestinal epithelial cells.
- To determine the role of MDC/CCL22 in T cell recruitment to the gut.
Main Methods:
- Analysis of MDC/CCL22 production in human colon epithelium and xenografts.
- Upregulation studies in colon epithelial cell lines using proinflammatory cytokines and bacteria.
- Investigation of nuclear factor (NF)-kappaB involvement in MDC/CCL22 regulation.
- Assessment of T cell chemotaxis towards epithelial cell supernatants.
Main Results:
- Constitutive MDC/CCL22 production by human colon epithelium in vivo.
- Upregulated MDC/CCL22 expression and secretion in response to inflammation and bacterial infection.
- NF-kappaB is a key regulator of MDC/CCL22 production.
- Epithelial MDC/CCL22 secretion promotes CCR4-positive T cell chemotaxis.
Conclusions:
- Intestinal epithelial cells constitutively and actively produce MDC/CCL22.
- MDC/CCL22 plays a crucial role in the trafficking of T cells to the intestinal mucosa.
- This chemokine is integral to the regulation of anti-inflammatory cytokine-producing T cells in the gut.
Abstract:
The intestinal mucosa contains a subset of lymphocytes that produce Th2 cytokines, yet the signals responsible for the recruitment of these cells are poorly understood. Macrophage-derived chemokine (MDC/CCL22) is a recently described CC chemokine known to chemoattract the Th2 cytokine producing cells that express the receptor CCR4. The studies herein demonstrate the constitutive production of MDC/CCL22 in vivo by human colon epithelium and by epithelium of human intestinal xenografts. MDC/CCL22 mRNA expression and protein secretion was upregulated in colon epithelial cell lines in response to proinflammatory cytokines or infection with enteroinvasive bacteria. Inhibition of nuclear factor (NF)-kappaB activation abolished MDC/CCL22 expression in response to proinflammatory stimuli, demonstrating that MDC/CCL22 is a NF-kappaB target gene. In addition, tumor necrosis factor-alpha-induced MDC/CCL22 secretion was differentially modulated by Th1 and Th2 cytokines. Supernatants from the basal, but not apical, side of polarized epithelial cells induced a MDC/CCL22-dependent chemotaxis of CCR4-positive T cells. These studies demonstrate the constitutive and regulated production by intestinal epithelial cells of a chemokine known to function in the trafficking of T cells that produce anti-inflammatory cytokines.
