Open Access Highly Accessed Research article

Importance of the interferon-α system in murine large intestine indicated by microarray analysis of commensal bacteria-induced immunological changes

Kaori Munakata1, Masahiro Yamamoto12, Naoko Anjiki3, Mitsue Nishiyama2, Sachiko Imamura2, Seiichi Iizuka2, Kiyoe Takashima1, Atsushi Ishige1, Kyoji Hioki4, Yasuyuki Ohnishi4 and Kenji Watanabe1*

Author Affiliations

1 Center for Kampo Medicine, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan

2 Pharmacology Research Department, Tsumura Central Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan

3 Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

4 Central Institute for Experimental Animals, 1430 Nogawa, Miyamae-ku, Kawasaki, Kanagawa 216-0001, Japan

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BMC Genomics 2008, 9:192  doi:10.1186/1471-2164-9-192

Published: 26 April 2008

Abstract

Background

Although microbiota play a critical role in the normal development and function of host immune systems, the underlying mechanisms, especially those involved in the large intestine (LI), remain unknown. In the present study, we performed transcriptome analysis of the LI of germ-free (GF) and specific pathogen-free (SPF) mice of the IQI strain, an inbred strain established from ICR mice.

Results

GeneChip analysis, quantitative real-time RT-PCR, and reconfirmation using bacteria-inoculated GF mice revealed differences in the expression levels of several immune-related genes, such as cryptdin-related sequences (CRS), certain subsets of type 1 interferon (IFN)-related genes, class Ib MHC molecules, and certain complements. LI expressed no authentic cryptdins but predominantly expressed CRS2, 4, and 7. The mRNA levels of IFN-related genes, including Irf7, Isgf3g, Ifit1 and Stat1, were lower in SPF- and flora-reconstituted mice. When an oral IFN-α inducer tilorone analog, R11567DA, was administered to SPF mice, IFN-α was induced rapidly in the LI at 4 h, whereas no IFN-α protein was detected in the small intestine (SI) or blood. In situ hybridization and immunohistochemistry suggested that the IFN-α production originated from Paneth cells in the SI, and portions of lamina proprial CD11b- or mPDCA1-positive cells in the LI.

Conclusion

The present study suggests that microbial colonization, while inducing the expression of anti-microbial peptides, results in the down-regulation of certain genes responsible for immune responses, especially for type I IFN synthesis. This may reflect the adaptation process of the immune system in the LI to prevent excessive inflammation with respect to continuous microbial exposure. Further, the repertoire of anti-microbial peptides and the extraordinary role of interferon producing cells in the LI have been found to be distinct from those in the SI.