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Regulatory Role of NKG2D+ NK Cells in Intestinal Lamina Propria by Secreting Double-Edged Th1 Cytokines in Ulcerative Colitis

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Regulatory Role of NKG2D+ NK Cells in Intestinal Lamina Propria by Secreting Double-Edged Th1 Cytokines in Ulcerative Colitis

Fan Wang et al. Oncotarget.

Abstract

The role of intestinal lamina propria (LP) NKG2D+ NK cells is unclear in regulating Th1/Th2 balance in ulcerative colitis (UC). In this study, we investigated the frequency of LP NKG2D+ NK cells in DSS-induced colitis model and intestinal mucosal samples of UC patients, as well as the secretion of Th1/Th2/Th17 cytokines in NK cell lines after MICA stimulation. The role of Th1 cytokines in UC was validated by bioinformatics analysis. We found that DSS-induced colitis in mice was characterized by a Th2-mediated process. In acute phrase, the frequency of LP NKG2D+ lymphocytes increased significantly and decreased in remission, while the frequency of LP NKG2D+ NK cells decreased significantly in acute phase and increased in remission. No obvious change was found in the frequency of total LP NK cells. Similarly, severe UC patients had a higher expression of mucosal NKG2D and a lower number of NKG2D+ NK cells than mild to moderate UC. In NK cell lines, the MICA stimulation could induce a predominant secretion of Th1 cytokines (TNF, IFN-γ). Furthermore, in bioinformatics analysis, mucosal Th1 cytokine of TNF, showed a double-edged role in UC when compared to the Th1-mediated disease of Crohn's colitis. In conclusion, LP NKG2D+ NK cells partially played a regulatory role in UC through secreting Th1 cytokines to regulate the Th2-predominant Th1/Th2 imbalance, despite of the concomitant pro-inflammatory effects of Th1 cytokines.

Keywords: NKG2D; intestinal lamina propria; natural killer cells; ulcerative colitis.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Evaluation of disease severity during DSS-induced colitis in mice
(A) Clinical scores. (B) Body weight. (C) Colon length. (D) Histologic characteristics (200-fold image magnification). AC: acute colitis, IR: in remission, HC: healthy controls, *: P < 0.05, **: P < 0.01, ***: P < 0.001, NS: not significant.
Figure 2
Figure 2. Change fold of cytokines
(A) Change fold of intestinal cytokines in DSS-induced colitis. (B) Change fold of mRNA levels of Th1/Th2/Th17 cytokines in NK-92 cell lines after MICA stimulation at different concentrations. AC: acute colitis, IR: in remission, HC: healthy controls, TNF: tumor necrosis factor, IFN: interferon, IL: interleukin, *: P < 0.05, **: P < 0.01, ***: P < 0.001, NS: not significant.
Figure 3
Figure 3. Frequency of NKG2D+ NK1.1+ CD3- cells in intestinal LPMCs
(A) Frequency of CD3- cells in LPMCs. (B) Frequency of NKG2D+ NK1.1+ cells in CD3- LPMCs. (C) Statistics. HC: healthy controls, AC: acute colitis, IR: in remission, LPMCs: lamina propria mononuclear cells, *: P < 0.05, **: P < 0.01, ***: P < 0.001, NS: not significant.
Figure 4
Figure 4. Immunofluorescence of mucosal NKG2D+ NKp46+ NK cells in UC patients of different disease activity
(A) Mild to moderate ulcerative colitis (UC). (B) Severe UC. (C) Statistics. Image magnification was 400-fold. Red light: NKG2D, Green light: NKp46, Yellow light: NKG2D and NKp46, UC, ulcerative colitis, *: P < 0.05, **: P < 0.01, ***: P < 0.001, NS: not significant.
Figure 5
Figure 5. Bioinformatics analysis of the role of TNF in UC and CDc
(A) The mRNA level of tumor necrosis factor in intestinal mucosa of UC and CDc before and after infliximab treatment. (B) Gene set enrichment analysis of biological processes related with TNF expression in UC and CDc (only list top 10). Responder: responder to infliximab treatment, Non-responder: non-responder to infliximab treatment; →: from the high mRNA level of TNF to the low level, TNF: tumor necrosis factor, UC: ulcerative colitis, CDc: Crohn's colitis.

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