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Exacerbation of Granuloma Formation in IL-1 Receptor Antagonist-Deficient Mice with Impaired Dendritic Cell Maturation Associated with Th2 Cytokine Production¹

Hisashi Iizasa^*,, Hiroyuki Yoneyama^*,, Naofumi Mukaida^¶, Yuki Katakoka, Makoto Naito^||, Nobuaki Yoshida, Emi Nakashima and Kouji Matsushima^2,*,

^* Department of Molecular Preventive Medicine, School of Medicine, and Division of Gene Expression and Regulation, Institute of Medical Science, University of Tokyo, and Department of Pharmaceutics, Kyoritsu University of Pharmacy, Tokyo, Japan; Solution Oriented Research for Science and Technology (SORST), Japan; ^¶ Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; and ^|| Second Department of Pathology, Niigata University School of Medicine, Niigata, Japan

Dendritic cell (DC) maturation at the site of inflammation and migration into draining lymph nodes is fundamental to initiate Ag-specific immune responses. Although several proinflammatory cytokines, including IL-1, are known to promote DC maturation in vitro, their contributions to DC activation and migration within peripheral inflamed tissue compartments are not yet fully understood. We show here that endogenous IL-1 receptor antagonist (IL-1ra) controls the activation state of liver-recruited DCs and their migration in a Propionibacterium acnes-induced murine granulomatous liver disease model. After P. acnes treatment, formation of portal tract-associated lymphoid tissue was conversely impaired in IL-1ra-deficient mice. IL-1ra-deficient mice developed hepatic granulomas within 3 days after P. acnes administration and showed a more pronounced granuloma formation than wild-type mice. Although sinusoidal granulomas contained numerous CD11c⁺ DCs at day 7, expressions of CCR7, IL-12p40 by these DCs were dramatically decreased in IL-1ra-deficient mice, suggesting aberrant DC maturation and sinusoid portal migration in the absence of endogenous IL-1ra. This was accompanied with enhanced intrahepatic Th2 cytokine production and severe hepatocellular damage. Thus, hepatocyte-derived IL-1ra may control optimal activation and migration of inflammatory DCs within the liver and thereby determine the local immune responses in granulomatous liver disease.

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