The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online 31 July 2006 doi:10.1084/jem.20060471
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 1875-1881
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BRIEF DEFINITIVE REPORT

 Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27

Stefan Wirtz1, Ingrid Tubbe1, Peter R. Galle1, Hans J. Schild2, Mark Birkenbach3, Richard S. Blumberg4, and Markus F. Neurath1

1 Laboratory of Immunology, I. Medical Clinic, and 2 Department of Immunology, University of Mainz, 55131 Mainz, Germany
3 Department of Pathology and Department of Anatomy, Eastern Virginia Medical School, Norfolk, VA 23501
4 Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Markus F. Neurath: neurath{at}1-med.klinik.uni-mainz.de

The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3–/– mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis.


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