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(Journal of Leukocyte Biology. 2005;78:1118-1126.)
© 2005 by Society for Leukocyte Biology

Involvement of neutrophil recruitment and protease-activated receptor 2 activation in the induction of IL-18 in mice

Keiji Ikawa^*,,, Takashi Nishioka^*,, Zhiqian Yu^*,, Yumiko Sugawara, Junichi Kawagoe^¶, Toshiaki Takizawa^¶, Valeria Primo, Boris Nikolic, Toshinobu Kuroishi^*, Takashi Sasano, Hidetoshi Shimauchi, Haruhiko Takada, Yasuo Endo^* and Shunji Sugawara^*,1

^* Divisions of Oral Immunology,
Periodontology and Endodontology, and
Oral Microbiology, Department of Oral Biology, and
Division of Oral Diagnosis, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan;
^¶ Tokyo New Drug Research Laboratories II, Pharmaceutical Division, Kowa Company Limited, Japan; and
The Renal Unit, Harvard Medical School/Massachusetts General Hospital, Boston

¹Correspondence: Division of Oral Immunology, Department of Oral Biology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: sugawars{at}mail.tains.tohoku.ac.jp

Activated neutrophils produce serine proteases, which activate cells through protease-activated receptor 2 (PAR2). As proteinase 3 (PR3) induces the secretion of interleukin (IL)-18 from epithelial cells in combination with lipopolysaccharide (LPS) in vitro, we examined whether neutrophils, serine proteases, and PAR2 are involved in the induction of serum IL-18 and IL-18-dependent liver injury in mice treated with heat-killed Propionibacterium acnes and LPS. LPS-induced serum IL-18 levels in P. acnes-primed mice were reduced significantly by anti-Gr-1 injection (depletion of neutrophils and macrophages) but not by a macrophage "suicide" technique, using liposomes encapsulating clodronate. The IL-18 induction was decreased significantly by coadministration of a serine protease inhibitor [Nafamostat mesilate (FUT-175)] with LPS. Serum levels of tumor necrosis factor and liver enzymes induced by P. acnes and LPS were abolished by anti-Gr-1 treatment, and concomitantly, liver injury (necrotic change and granuloma formation) and Gr-1⁺ cell infiltration into the liver were prevented by the treatment. A deficiency of PAR2 in mice significantly impaired IL-18 induction by treatment with P. acnes and LPS, and only slight pathological changes in hepatic tissues occurred in the PAR2-deficient mice treated with P. acnes and LPS. Furthermore, coadministration of exogenous murine PR3 or a synthetic PAR2 agonist (ASKH95) with LPS in the anti-Gr-1-treated mice restored the serum IL-18 levels to those in control mice treated with P. acnes and LPS. These results indicate that neutrophil recruitment and PAR2 activation by neutrophil serine proteases are critically involved in the induction of IL-18 and IL-18-dependent liver injury in vivo.

Key Words: PMN • serine proteases • G protein-coupled receptor • cytokine • inflammation

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