BACKGROUND: The G protein alpha subunit type-2 (Galpha(i)2)-deficient mouse develops inflammatory bowel disease (IBD) with increased severity in mice on a 129SvEv (129) background compared to the C57BL/6 (B6) background. Since dendritic cells (DCs) are key cells of innate immunity, we determined whether Galpha(i)2(-/-) DCs have functional defects, influenced by strain background, that predispose to IBD. METHODS: By breeding these strains to homozygosity for the first time, it became possible to study innate immunity in this animal model with more precision than ever before. Immature DCs were generated using bone marrow monoblasts cultured in the presence of GM-CSF (BMDCs), DC subsets sorted and responses to TLR9 activation were assayed. RESULTS: In contrast to Galpha(i)2(-/-) B6, Galpha(i)2(-/-) 129 mice display accelerated onset and increased severity of colitis, abnormal mucosal DC distribution, accompanied by preponderance for Th1 and Th17-associated gut cytokine expression. TLR9 activation of BMDCs induces sustained p38 MAPK activation and greater Th1- and Th17-type cytokine secretion in both strains of Galpha(i)2-deficient compared to wildtype BMDCs. However, only B6 Galpha(i)2(-/-) BMDCs concomitantly produces IL-10 while Galpha(i)2(-/-) 129 BMDCs do not. CONCLUSIONS: Loss of Galpha(i)2 promotes a Th1/Th17 phenotype and relative IL-10 insufficiency in Galpha(i)2(-/-) 129 BMDCs may account for the striking difference in disease.
BACKGROUND: The G protein alpha subunit type-2 (Galpha(i)2)-deficient mouse develops inflammatory bowel disease (IBD) with increased severity in mice on a 129SvEv (129) background compared to the C57BL/6 (B6) background. Since dendritic cells (DCs) are key cells of innate immunity, we determined whether Galpha(i)2(-/-) DCs have functional defects, influenced by strain background, that predispose to IBD. METHODS: By breeding these strains to homozygosity for the first time, it became possible to study innate immunity in this animal model with more precision than ever before. Immature DCs were generated using bone marrow monoblasts cultured in the presence of GM-CSF (BMDCs), DC subsets sorted and responses to TLR9 activation were assayed. RESULTS: In contrast to Galpha(i)2(-/-) B6, Galpha(i)2(-/-) 129 mice display accelerated onset and increased severity of colitis, abnormal mucosal DC distribution, accompanied by preponderance for Th1 and Th17-associated gut cytokine expression. TLR9 activation of BMDCs induces sustained p38 MAPK activation and greater Th1- and Th17-type cytokine secretion in both strains of Galpha(i)2-deficient compared to wildtype BMDCs. However, only B6 Galpha(i)2(-/-) BMDCs concomitantly produces IL-10 while Galpha(i)2(-/-) 129 BMDCs do not. CONCLUSIONS: Loss of Galpha(i)2 promotes a Th1/Th17 phenotype and relative IL-10insufficiency in Galpha(i)2(-/-) 129 BMDCs may account for the striking difference in disease.
Authors: Holm H Uhlig; Brent S McKenzie; Sophie Hue; Claire Thompson; Barbara Joyce-Shaikh; Renata Stepankova; Nicolas Robinson; Sofia Buonocore; Helena Tlaskalova-Hogenova; Daniel J Cua; Fiona Powrie Journal: Immunity Date: 2006-08 Impact factor: 31.745
Authors: Carissa M Thomas; Teresa Hong; Jan Peter van Pijkeren; Peera Hemarajata; Dan V Trinh; Weidong Hu; Robert A Britton; Markus Kalkum; James Versalovic Journal: PLoS One Date: 2012-02-22 Impact factor: 3.240
Authors: Ajay S Gulati; Michael T Shanahan; Janelle C Arthur; Emily Grossniklaus; Richard J von Furstenberg; Lieselotte Kreuk; Susan J Henning; Christian Jobin; R Balfour Sartor Journal: PLoS One Date: 2012-02-27 Impact factor: 3.240