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Extracellular nucleotides regulate CCL20 release from human primary airway epithelial cells, monocytes and monocyte‐derived dendritic cells
Author(s) -
Marcet Brice,
Horckmans Michael,
Libert Frédérick,
Hassid Sergio,
Boeynaems JeanMarie,
Communi Didier
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20979
Subject(s) - ccl20 , chemokine , microbiology and biotechnology , p2y receptor , cytokine , monocyte , tlr2 , chemistry , biology , receptor , extracellular , chemokine receptor , signal transduction , immunology , purinergic receptor , biochemistry , tlr4
Extracellular nucleotides regulate ion transport and mucociliary clearance in human airway epithelial cells (HAECs) via the activation of P2 receptors, especially P2Y 2 . Therefore, P2Y 2 receptor agonists represent potential pharmacotherapeutic agents to treat cystic fibrosis (CF). Nucleotides also modulate inflammatory properties of immune cells like dendritic cells (DCs), which play an important role in mucosal immunity. Using DNA‐microarray experiments, quantitative RT‐PCR and cytokine measurements, we show here that UTP up‐regulated ∼2‐ to 3‐fold the antimicrobial chemokine CCL20 expression and release in primary HAECs cultured on permeable supports at an air–liquid interface (ALI). Both P2Y 2 (ATPγS, UTP, INS365) and P2Y 6 (UDP, INS48823) agonists increased CCL20 release. UTP‐induced CCL20 release was insensitive to NF‐κB pathway inhibitors but sensitive to inhibitors of ERK1/2 and p38/MAPK pathways. Furthermore, UTP had no effect on interleukin‐(IL)‐8 release and reduced the release of both CCL20 and IL‐8 induced by TNF‐α and LPS. Accordingly, UTP reduced the capacity of basolateral supernatants of HAECs treated with TNF‐α or LPS to induce the chemoattraction of both CD4 + T lymphocytes and neutrophils. In addition, we show that, in monocyte‐derived DCs, ATPγS, and UDP but not UTP/INS365‐stimulated CCL20 release. Likewise, UDP but not ATPγS was also able to increase CCL20 release from monocytes. Pharmacological experiments suggested an involvement of P2Y 11 or P2Y 6 receptors through NF‐κB, ERK1/2, and p38/MAPK pathways. Altogether, our data demonstrate that nucleotides may modulate chemokine release and leukocyte recruitment in inflamed airways by acting on both epithelial and immune cells. Our results could be relevant for further clinical investigations in CF. J. Cell. Physiol. 211: 716–727, 2007. © 2007 Wiley‐Liss, Inc.