TNFRP55 DEFICIENCY AUGMENTS TH1 AND TH17 RESPONSES DURING DEVELOPMENT OF ARTHRITIS

RICARDO J. ELIÇABE; ETHELINA CARGNELUTTI; MARÍA I. SERER; PATRICIA STEGE; SUSANA VALDÉZ; GABRIEL A. RABINOVICH; MARÍA S. DI GENARO

Berlín, Alemania

Congreso; 2nd European Congress of Immunology (ECI Berlín,2009); 2009

Sociedad Europea de Inmunología

Reactive arthritis (ReA) is an inflammatory arthritis that arises after certain types of gastrointestinal or genitourinary infectious. The pathogenesis of ReA is incompletely understood. Th1 and Th17 cells are associated with chronic inflammation. The objective was to determine the IL-17 and IFN-gamma contribution in Yersinia-induced ReA in TNFRp55 -/- mice. We used C57BL/6 TNFRp55 -/- and wild-type (WT) mice. The animals were orally infected with Y. enterocolitica O:3, and arthritis progression was assessed using clinical score and histological analysis. Yersinia LPS in the joint was investigated by micellar electrokinetic chromatography (MEKC). Homogenates of joint, mesenteric lymph nodes (MLN) and inguinal lymph nodes (ILN) were obtained at different days after infection (7, 14 and 21), and IFN-gamma, IL-17, TGF-beta, IL-6, IL-1beta and IL-10 levels were quantified by ELISA. Spleen cells from WT and TNFRp55 -/- mice were re-stimulated in vitro with heat-killed Yersinia (HKY) and the supernatants were examined for IFN-gamma and IL-17 production. Differences between the groups were tested for significance by Mann Whitney U test. A p value less than 0.05 was considered statistically significant. We found higher severity of ReA in TNFRp55 -/- compared with WT mice. LPS was detected in joint of the mice. When we compared local cytokine profile in the joint of TNFRp55 -/- with WT mice, we found higher articular IFN-gamma and IL-17 levels in TNFRp55 -/- mice at day 14 (p< 0.02) and 21 (p< 0.03) after infection, respectively. We demonstrated early correlation between cytokine production in MLN and ILN. When systemic cytokine production was examined, IL-17 and IFN-gamma levels were increased in knockout mice (p< 0.05). Association between IL-17, IL-6 and TGF-beta levels was observed. Inflammatory response dominated by articular IL-17, IL-6 and IL-1beta, including IFN-gamma in ILN, was detected in the chronic phase of arthritis in TNFRp55-/- mice. Altered IL-10 production and higher IL-12/IL23 p40 level was found TNFRp55 -/- mice (p< 0.05). These data demonstrate redundant pathways, including both IL-17 and IFN-gamma, may be used to mediate inflammation in absent of TNFRp55. One way by which TNFRp55 signaling regulates Th1 and Th17 responses is down-regulating p40. These results provide further understanding of the cytokine interplay in ReA.