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Endotoxin-Induced Chemokine Expression in Murine Peritoneal Mesothelial Cells: The Role of Toll-Like Receptor 4

Sawako Kato^*, Yukio Yuzawa^*, Naotake Tsuboi^*,, Shoichi Maruyama^*, Yoshiki Morita^*, Tetsuya Matsuguchi and Seiichi Matsuo^*

*Division of Clinical Immunology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, and Department of Host Defense, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Correspondence to: Dr. Yukio Yuzawa, Division of Clinical Immunology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho Showa-ku, Nagoya, Aichi, 466-8550, Japan. Phone: +81-52-744-2192; Fax: +81-52-744-2209, E-mail: yukio{at}med.nagoya-u.ac.jp

ABSTRACT. Acute peritonitis, in which peritoneal mesothelial cells are directly exposed to bacterial components, is a major cause of peritoneal dysfunction in continuous ambulatory peritoneal dialysis patients. We have previously shown that Toll-like receptors (TLR) are expressed in kidney cells, and LPS induces TLR4-dependent chemokine production in tubular epithelial cells. The present work was designed to investigate the involvement of TLR, especially TLR4, in the lipid A-mediated chemokine production by murine peritoneal mesothelial cells (MPMC). A primary cell culture of MPMC from C3H/HeN mice (wild-type mice; LPS sensitive) and from C3H/HeJ mice (containing a point mutation of TLR4; LPS hyposensitive) was established. The expression profile of the TLR family and their accessory molecules, CD14 and MD-2, which are requisite for the LPS signaling pathway, was examined by RT-PCR, Northern blot test, and immunohistochemical staining. Synthetic lipid A-mediated chemokine production by MPMC was studied. The involvement of MAP kinase family (ERK, JNK, and p38 mitogen-activated protein kinase) and nuclear factor (NF)-B in these processes was also studied. MPMC constitutively express TLR4, CD14, and MD-2. A prominent induction of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein (MIP)-2 by MPMC was detected after lipid A stimulation and was strictly dependent on TLR4. Furthermore, TLR4-dependent chemokine production followed by leukocyte influx into the peritoneal cavity was also confirmed in vivo after stimulation with LPS. mRNA expression of MCP-1 was abolished by NF-B inhibition, but were not affected by the inhibition of ERK, JNK, or p38. As compared with MCP-1, MIP-2 mRNA expression was inhibited by a high dose of curcumin but not by NF-B decoy oligodeoxynucleotide and individual inhibitions of MAP kinase, suggesting that the additional signaling pathway with NF-B might be involved in mRNA expression of MIP-2. These show that TLR4 is directly involved in the production of MCP-1 and MIP-2 by MPMC in a NF-B-dependent manner, but the process does not require any MAP kinase activation. The results provide a candidate molecular target in prevention of it.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673