Aberrant activation of nuclear factor of activated T cell 2 in lamina propria mononuclear cells in ulcerative colitis.
OBJECTIVE
To investigate the role of nuclear factor of activated T cell 2 (NFAT2), the major NFAT protein in peripheral T cells, in sustained T cell activation and intractable inflammation in human ulcerative colitis (UC).


METHODS
We used two-dimensional gel-electrophoresis, immunohistochemistry, double immunohistochemical staining, and confocal microscopy to inspect the expression of NFAT2 in 107, 15, 48 and 5 cases of UC, Crohn's disease (CD), non-specific colitis, and 5 healthy individuals, respectively.


RESULTS
Up-regulation with profound nucleo-translocation/activation of NFAT2 of lamina propria mononuclear cells (LPMC) of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC, as compared to CD or NC (P < 0.001, Kruskal-Wallis test). Nucleo-translocation/activation of NFAT2 primarily occurred in CD8+T, but was less prominent in CD4+ T cells or CD20+B cells. It was strongly associated with the disease activity, including endoscopic stage (tau = 0.2145, P = 0.0281) and histologic grade (tau = 0.4167, P < 0.001).


CONCLUSIONS
We disclose for the first time the nucleo-translocation/activation of NFAT2 in lamina propria mononuclear cells in ulcerative colitis. Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity. Since activation of NFAT2 is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways, our results not only provide new insights into the mechanism for sustained intractable inflammation, but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.
Shih
Tsung-Chieh
TC
Clinical Proteomics Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
Hsieh
Sen-Yung
SY
Hsieh
Yi-Yueh
YY
Chen
Tse-Chin
TC
Yeh
Chien-Yu
CY
Lin
Chun-Jung
CJ
Lin
Deng-Yn
DY
Chiu
Cheng-Tang
CT
D000328:Adult; D018951:Antigens, CD20 / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002467:Cell Nucleus / Q000276:immunology; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003113:Colonoscopy; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D050778:NFATC Transcription Factors / Q000032:analysis*; D040901:Proteomics / Q000379:methods; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015854:Up-Regulation
D018951:Antigens, CD20; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human