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Infection and Immunity, September 2008, p. 4206-4213, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.01209-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Interleukin-17 Receptor Plays a Gender-Dependent Role in Host Protection against Porphyromonas gingivalis-Induced Periodontal Bone Loss{triangledown}

Jeffrey J. Yu,1 Matthew J. Ruddy,1 Heather R. Conti,2 Kanitsak Boonanantanasarn,2 and Sarah L. Gaffen1,2*

Department of Microbiology and Immunology,1 Department of Oral Biology, University at Buffalo, SUNY, Buffalo, New York2

Received 3 September 2007/ Returned for modification 10 October 2007/ Accepted 18 June 2008

Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4+ Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response. The role of IL-17 in PD is controversial. Whereas elevated IL-17 levels have been found in humans with severe PD, we recently reported that female C57BL/6J mice lacking the IL-17 receptor (IL-17RAKO) are significantly more susceptible to PD bone loss due to defects in the chemokine-neutrophil axis (J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen, Blood 109:3794-3802, 2007). Since different mouse strains exhibit differences in susceptibility to PD as well as Th1/Th2 cell skewing, we crossed the IL-17RA gene knockout onto the BALB/c background and observed a similar enhancement in alveolar bone loss following P. gingivalis infection. Unexpectedly, in both strains IL-17RAKO female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RAKO mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Gro{alpha} and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.

* Corresponding author. Present address: University of Pittsburgh, Division of Rheumatology and Clinical Immunology, S708 Biomedical Science Tower, 3500 Terrace St., Pittsburgh, PA 15261. Phone: (412) 383-8903. Fax: (412) 383-8864. E-mail: sig65{at}pitt.edu

{triangledown} Published ahead of print on 30 June 2008.

Editor: J. L. Flynn

Infection and Immunity, September 2008, p. 4206-4213, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.01209-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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