Interplay between Th1 and Th17 effector T-cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the G i2-deficient mouse

Abstract

Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.

Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis

“…Page%29%of%44% % associated with the poor prognosis of patients 30 . Furthermore, the loss of GNAI2 in Gnai2 -/mice leads to increased CCL2 in chronic inflammation 31 .…”

“…We next sought to address the regulatory mechanism of HSC activation by GNAI2. Chemokine CCL2, one of the key regulators of inflammation and liver fibrosis 30 , has previously been reported to be elevated upon knockdown of Gnai2 in mice 31 . Since we observed regulation of Gnai2 by miR-221-3p, we Page%24%of%44% % therefore reasoned that CCL2 could be a key component of miR-221-3p-GNAI2 signaling.…”

The Immunostimulatory and Anti-tumor Activities of Polysaccharide from <i>Agaricus bisporus</i> (brown)

“…Spleen and thymus are the main immune organs, and their indexes can reflect the condition of immunologic function [26,27]. The main function of thymus is producing T-lymphocytes (T cells), which are critical cells of the adaptive immune system and responsible for cellular immunity.…”

IL-21 and Related Diseases

“…Colonic IL-21 expression increased in the Gαi2-deficient mice which spontaneously developed severe colitis and colon cancer [81]. IL-21 was produced in excess in the gut of patients with UC-associated colon cancer [82].…”