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Liver myofibroblasts from hepatitis B related liver failure patients may regulate natural killer cell function via PGE2.

Zhang M, Wang F, Chong Y, Tai Q, Zhao Q, Zheng Y, Peng L, Lin S, Gao Z - J Transl Med (2014)

Bottom Line: Natural killer (NK) cells are abundant in the liver and constitute a major innate immune component that contributes to immune-mediated liver injury.The inhibitory effect of LMFs on NK cells correlated with their ability to produce prostaglandin (PG) E2.These data suggest that LMFs may protect against immune-mediated liver injury in hepatitis B related LF patients by inhibiting NK cell function via PGE2.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. zm20051208@163.com.

ABSTRACT

Background: Natural killer (NK) cells are abundant in the liver and constitute a major innate immune component that contributes to immune-mediated liver injury. However, few studies have investigated the phenotypes and functions of NK cells involved in hepatitis B related liver failure (LF), and the precise mechanism underlying NK cell regulation is not fully understood.

Methods: We detected the percentage and function of peripheral NK cells both in hepatitis B related LF patients and healthy volunteers by flow cytometry and isolated the liver myofibroblasts (LMFs) from hepatitis B related LF livers. To determine the possible effects of LMFs on NK cells, mixed cell cultures were established in vitro.

Results: We found a down-regulated percentage of peripheral NK cells in hepatitis B related LF patients, and their NK cells also displayed decreased activated natural cytotoxicity receptors (NCRs) and cytokine production. In a co-culture model, LMFs sharply attenuated IL-2-induced NK cell triggering receptors, cytotoxicity, and cytokine production. The inhibitory effect of LMFs on NK cells correlated with their ability to produce prostaglandin (PG) E2.

Conclusion: These data suggest that LMFs may protect against immune-mediated liver injury in hepatitis B related LF patients by inhibiting NK cell function via PGE2.

No MeSH data available.


Related in: MedlinePlus

The variation in peripheral blood NK cells between hepatitis B related LF patients and healthy controls. (A) Representative dot plots of CD3+ and CD56+ staining in PBMCs isolated from healthy control subjects (HC) and hepatitis B related LF patients (LF). The total number of 1 × 105 cells per gate was analyzed. The values in the quadrants represent the percentages of CD3-CD56+ NK cells, CD3+CD56+ NKT cells, CD3+CD56- T cells, and CD3-CD56- cells. (B) The summarized data show the percentages of CD3-CD56+ NK cells and CD3+ T cells in HC and LF. (C) CD3-CD56+ NK cells were gated. Representative primary FACS histograms depict the expression of activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by peripheral NK cells from LF (open profiles with solid lines) and HC (gray filled profiles). Open profiles with dotted lines show the isotype control. (D) Pooled data show the MFI of peripheral NK cells expressing activation receptors, as well as perforin, granzyme B and IFN-γ production from HC (open profiles) and LF (black profiles). The values given in B and D represent the means ± SEM of five separate experiments. *P <0.05 and **P <0.01 indicate significant differences between HC and LF (B and D).
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Fig1: The variation in peripheral blood NK cells between hepatitis B related LF patients and healthy controls. (A) Representative dot plots of CD3+ and CD56+ staining in PBMCs isolated from healthy control subjects (HC) and hepatitis B related LF patients (LF). The total number of 1 × 105 cells per gate was analyzed. The values in the quadrants represent the percentages of CD3-CD56+ NK cells, CD3+CD56+ NKT cells, CD3+CD56- T cells, and CD3-CD56- cells. (B) The summarized data show the percentages of CD3-CD56+ NK cells and CD3+ T cells in HC and LF. (C) CD3-CD56+ NK cells were gated. Representative primary FACS histograms depict the expression of activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by peripheral NK cells from LF (open profiles with solid lines) and HC (gray filled profiles). Open profiles with dotted lines show the isotype control. (D) Pooled data show the MFI of peripheral NK cells expressing activation receptors, as well as perforin, granzyme B and IFN-γ production from HC (open profiles) and LF (black profiles). The values given in B and D represent the means ± SEM of five separate experiments. *P <0.05 and **P <0.01 indicate significant differences between HC and LF (B and D).

Mentions: To better understand the potential role of NK cells in the pathogenesis of hepatitis B related LF, we first detected the distribution and phenotype of peripheral NK cells in these patients. We dissected the subtypes of peripheral blood leukocytes in 20 hepatitis B related LF patients and 20 healthy controls by flow cytometry analysis for CD56+CD3- NK cells and CD3+ T cells. In comparison with healthy control subjects, the percentages of NK cells and CD3+ T cells were significantly reduced in hepatitis B related LF patients (Figure 1A and B). We further analyzed the expression of NK activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by NK cells in the two groups of individuals. As illustrated in Figure 1C and D, the expression of most of the activation markers was down-regulated except for NKG2D and NKp46, and cytolytic granules and IFN-γ production were inhibited in the peripheral NK cells of hepatitis B related LF patients, suggesting their dysfunctional status.Figure 1


Liver myofibroblasts from hepatitis B related liver failure patients may regulate natural killer cell function via PGE2.

Zhang M, Wang F, Chong Y, Tai Q, Zhao Q, Zheng Y, Peng L, Lin S, Gao Z - J Transl Med (2014)

The variation in peripheral blood NK cells between hepatitis B related LF patients and healthy controls. (A) Representative dot plots of CD3+ and CD56+ staining in PBMCs isolated from healthy control subjects (HC) and hepatitis B related LF patients (LF). The total number of 1 × 105 cells per gate was analyzed. The values in the quadrants represent the percentages of CD3-CD56+ NK cells, CD3+CD56+ NKT cells, CD3+CD56- T cells, and CD3-CD56- cells. (B) The summarized data show the percentages of CD3-CD56+ NK cells and CD3+ T cells in HC and LF. (C) CD3-CD56+ NK cells were gated. Representative primary FACS histograms depict the expression of activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by peripheral NK cells from LF (open profiles with solid lines) and HC (gray filled profiles). Open profiles with dotted lines show the isotype control. (D) Pooled data show the MFI of peripheral NK cells expressing activation receptors, as well as perforin, granzyme B and IFN-γ production from HC (open profiles) and LF (black profiles). The values given in B and D represent the means ± SEM of five separate experiments. *P <0.05 and **P <0.01 indicate significant differences between HC and LF (B and D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4232720&req=5

Fig1: The variation in peripheral blood NK cells between hepatitis B related LF patients and healthy controls. (A) Representative dot plots of CD3+ and CD56+ staining in PBMCs isolated from healthy control subjects (HC) and hepatitis B related LF patients (LF). The total number of 1 × 105 cells per gate was analyzed. The values in the quadrants represent the percentages of CD3-CD56+ NK cells, CD3+CD56+ NKT cells, CD3+CD56- T cells, and CD3-CD56- cells. (B) The summarized data show the percentages of CD3-CD56+ NK cells and CD3+ T cells in HC and LF. (C) CD3-CD56+ NK cells were gated. Representative primary FACS histograms depict the expression of activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by peripheral NK cells from LF (open profiles with solid lines) and HC (gray filled profiles). Open profiles with dotted lines show the isotype control. (D) Pooled data show the MFI of peripheral NK cells expressing activation receptors, as well as perforin, granzyme B and IFN-γ production from HC (open profiles) and LF (black profiles). The values given in B and D represent the means ± SEM of five separate experiments. *P <0.05 and **P <0.01 indicate significant differences between HC and LF (B and D).
Mentions: To better understand the potential role of NK cells in the pathogenesis of hepatitis B related LF, we first detected the distribution and phenotype of peripheral NK cells in these patients. We dissected the subtypes of peripheral blood leukocytes in 20 hepatitis B related LF patients and 20 healthy controls by flow cytometry analysis for CD56+CD3- NK cells and CD3+ T cells. In comparison with healthy control subjects, the percentages of NK cells and CD3+ T cells were significantly reduced in hepatitis B related LF patients (Figure 1A and B). We further analyzed the expression of NK activation markers, including NKp30, NKp44, NKp46, NKG2D, DNAM-1, CD69, cytolytic granules (perforin and granzyme B) and cytokine (IFN-γ) production by NK cells in the two groups of individuals. As illustrated in Figure 1C and D, the expression of most of the activation markers was down-regulated except for NKG2D and NKp46, and cytolytic granules and IFN-γ production were inhibited in the peripheral NK cells of hepatitis B related LF patients, suggesting their dysfunctional status.Figure 1

Bottom Line: Natural killer (NK) cells are abundant in the liver and constitute a major innate immune component that contributes to immune-mediated liver injury.The inhibitory effect of LMFs on NK cells correlated with their ability to produce prostaglandin (PG) E2.These data suggest that LMFs may protect against immune-mediated liver injury in hepatitis B related LF patients by inhibiting NK cell function via PGE2.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China. zm20051208@163.com.

ABSTRACT

Background: Natural killer (NK) cells are abundant in the liver and constitute a major innate immune component that contributes to immune-mediated liver injury. However, few studies have investigated the phenotypes and functions of NK cells involved in hepatitis B related liver failure (LF), and the precise mechanism underlying NK cell regulation is not fully understood.

Methods: We detected the percentage and function of peripheral NK cells both in hepatitis B related LF patients and healthy volunteers by flow cytometry and isolated the liver myofibroblasts (LMFs) from hepatitis B related LF livers. To determine the possible effects of LMFs on NK cells, mixed cell cultures were established in vitro.

Results: We found a down-regulated percentage of peripheral NK cells in hepatitis B related LF patients, and their NK cells also displayed decreased activated natural cytotoxicity receptors (NCRs) and cytokine production. In a co-culture model, LMFs sharply attenuated IL-2-induced NK cell triggering receptors, cytotoxicity, and cytokine production. The inhibitory effect of LMFs on NK cells correlated with their ability to produce prostaglandin (PG) E2.

Conclusion: These data suggest that LMFs may protect against immune-mediated liver injury in hepatitis B related LF patients by inhibiting NK cell function via PGE2.

No MeSH data available.


Related in: MedlinePlus