title: The interleukin-17 receptor plays a gender-dependent role in host protection against Porphyromonas gingivalis-induced periodontal bone loss.
abstract: 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-17RA(KO)) 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-17RA(KO) female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RA(KO) mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Groalpha 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.
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, SUNY, Buffalo, New York, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Yu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ruddy
authors.forename: Heather R
authors.initials: HR
authors.lastname: Conti
authors.forename: Kanitsak
authors.initials: K
authors.lastname: Boonanantanasarn
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D016301:Alveolar Bone Loss / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D016866:Bacteroidaceae Infections / Q000276:immunology / Q000473:pathology; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016966:Porphyromonas gingivalis / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000276:immunology*; D012737:Sex Factors
chemical_list: D000907:Antibodies, Bacterial; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D007074:Immunoglobulin G; D053722:Receptors, Interleukin-17; D016179:Granulocyte Colony-Stimulating Factor