Role of rapamycin in cholangiocytes regeneration after liver transplantation
OBJECTIVE: To investigate the role of IL-6/STAT3 pathway in the proliferation of cholangiocytes after liver transplantation and determine whether or not rapamycin (RPM) depresses the regeneration of cholangiocytes by blocking the activation of STAT3.
METHODS: Rats were randomized into OLT-1 h and OLT-12 h groups (supplied livers preserved for 1 or 12 h), anti-sIL-6R group (rats of the OLT-12 h group injected intravenously with 16.7 µg/kg anti-rat sIL-6R antibody at 1 hour pre-operation and daily post-operation), RPM group (rats of the OLT-12 h group injected intraperitoneally with 0.05 mg/kg RPM for 3 days pre-operation and daily post-operation) and sham group (transverse laparotomy and closure without liver manipulation). At 1, 3, 7, 14 d post-operation, the IL-6 concentration in liver homogenate and cholangiocytes proliferation were detected by ELISA (enzyme linked immunosorbent assay) and histochemistry respectively. The expressions of IL-6 mRNA, phosphorylated-STAT3 and cyclin D1 protein in cholangiocytes were determined by real-time RT-PCR (reverse transcription-polymerase chain reaction) or Western blot. The DNA binding activity of STAT3 was determined by electrophoretic mobility shift assay. The serum concentrations of ALP (alkaline phosphatase) and GGT (γ-glutamyltransferase) were also measured.
RESULTS: The minimal expressions of IL-6, p-STAT3, cyclin D1 and DNA binding activity of STAT3 were detected in OLT-1h group. And a slight increase of IOD (integral optical density) ratio (38 ± 10 and 22 ± 7) indicated a mild cholangiocytes proliferation. The concentrations of GGT were (69 ± 6) U/L, (34 ± 4) U/L and ALP (86 ± 9) U/L, (45 ± 3) U/L. The expression of IL-6 in liver homogenate were (273 ± 20) ng/g, (159 ± 18) ng/g and 0.40 ± 0.04, 0.23 ± 0.04 in cholangiocytes. The expressions of P-STAT3 were 0.420 ± 0.023 and 0.230 ± 0.040 in cholangiocytes and cyclin D1 0.580 ± 0.023 and 0.420 ± 0.015 respectively. Cholangiocytes responded to extended cold preservation with severe bile duct injures and marked increases in IL-6 secretion, p-STAT3 and cyclin D1 protein expression and DNA binding activity of STAT3, followed by compensatory cholangiocytes regeneration. Meanwhile biochemical index and morphology indicated that bile duct injury recovered at 14 d post-operation. The IOD ratios were 38 ± 10 and 22 ± 7 respectively. The expressions of IL-6 were (659 ± 28) and (446 ± 23) ng/g in liver homogenate and 0.73 ± 0.06 and 0.54 ± 0.04 in cholangiocytes. The expression of P-STAT3 were 0.72 ± 0.04 and 0.58 ± 0.06 in cholangiocytes and cyclin D1 0.88 ± 0.04 and 0.74 ± 0.07 respectively. However, anti-sIL-6R inhibited the cholangiocytes proliferation and reduced the expressions of IL-6, STAT3 and cyclin D1. The DNA binding activity of STAT3 with cellular injury and the increases of serum ALP or GGT were also abrogated by the administration of anti-sIL-6R. With similar results, the RPM treatment had insignificant effects on the expression of IL-6.
CONCLUSION: The IL-6/STAT3 pathway initiates the cholangiocytes regeneration after liver transplantation so as to accelerate the biliary recovery. However RPM represses the cholangiocytes regeneration by inhibiting the STAT3 activation. It may have a negative effect on the healing and recovery of bile ducts in grafts with extended cold preservation.
Medienart: |
Artikel |
---|
Erscheinungsjahr: |
2011 |
---|---|
Erschienen: |
2011 |
Enthalten in: |
Zur Gesamtaufnahme - volume:91 |
---|---|
Enthalten in: |
Zhonghua yi xue za zhi - 91(2011), 22 vom: 14. Juni, Seite 1523-8 |
Sprache: |
Chinesisch |
---|
Beteiligte Personen: |
Chen, Li-ping [VerfasserIn] |
---|
Themen: |
English Abstract |
---|
Anmerkungen: |
Date Completed 02.04.2012 Date Revised 21.11.2013 published: Print Citation Status MEDLINE |
---|
Förderinstitution / Projekttitel: |
|
---|
PPN (Katalog-ID): |
NLM211440213 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM211440213 | ||
003 | DE-627 | ||
005 | 20231224013539.0 | ||
007 | tu | ||
008 | 231224s2011 xx ||||| 00| ||chi c | ||
028 | 5 | 2 | |a pubmed24n0705.xml |
035 | |a (DE-627)NLM211440213 | ||
035 | |a (NLM)21914363 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a chi | ||
100 | 1 | |a Chen, Li-ping |e verfasserin |4 aut | |
245 | 1 | 0 | |a Role of rapamycin in cholangiocytes regeneration after liver transplantation |
264 | 1 | |c 2011 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
338 | |a Band |b nc |2 rdacarrier | ||
500 | |a Date Completed 02.04.2012 | ||
500 | |a Date Revised 21.11.2013 | ||
500 | |a published: Print | ||
500 | |a Citation Status MEDLINE | ||
520 | |a OBJECTIVE: To investigate the role of IL-6/STAT3 pathway in the proliferation of cholangiocytes after liver transplantation and determine whether or not rapamycin (RPM) depresses the regeneration of cholangiocytes by blocking the activation of STAT3 | ||
520 | |a METHODS: Rats were randomized into OLT-1 h and OLT-12 h groups (supplied livers preserved for 1 or 12 h), anti-sIL-6R group (rats of the OLT-12 h group injected intravenously with 16.7 µg/kg anti-rat sIL-6R antibody at 1 hour pre-operation and daily post-operation), RPM group (rats of the OLT-12 h group injected intraperitoneally with 0.05 mg/kg RPM for 3 days pre-operation and daily post-operation) and sham group (transverse laparotomy and closure without liver manipulation). At 1, 3, 7, 14 d post-operation, the IL-6 concentration in liver homogenate and cholangiocytes proliferation were detected by ELISA (enzyme linked immunosorbent assay) and histochemistry respectively. The expressions of IL-6 mRNA, phosphorylated-STAT3 and cyclin D1 protein in cholangiocytes were determined by real-time RT-PCR (reverse transcription-polymerase chain reaction) or Western blot. The DNA binding activity of STAT3 was determined by electrophoretic mobility shift assay. The serum concentrations of ALP (alkaline phosphatase) and GGT (γ-glutamyltransferase) were also measured | ||
520 | |a RESULTS: The minimal expressions of IL-6, p-STAT3, cyclin D1 and DNA binding activity of STAT3 were detected in OLT-1h group. And a slight increase of IOD (integral optical density) ratio (38 ± 10 and 22 ± 7) indicated a mild cholangiocytes proliferation. The concentrations of GGT were (69 ± 6) U/L, (34 ± 4) U/L and ALP (86 ± 9) U/L, (45 ± 3) U/L. The expression of IL-6 in liver homogenate were (273 ± 20) ng/g, (159 ± 18) ng/g and 0.40 ± 0.04, 0.23 ± 0.04 in cholangiocytes. The expressions of P-STAT3 were 0.420 ± 0.023 and 0.230 ± 0.040 in cholangiocytes and cyclin D1 0.580 ± 0.023 and 0.420 ± 0.015 respectively. Cholangiocytes responded to extended cold preservation with severe bile duct injures and marked increases in IL-6 secretion, p-STAT3 and cyclin D1 protein expression and DNA binding activity of STAT3, followed by compensatory cholangiocytes regeneration. Meanwhile biochemical index and morphology indicated that bile duct injury recovered at 14 d post-operation. The IOD ratios were 38 ± 10 and 22 ± 7 respectively. The expressions of IL-6 were (659 ± 28) and (446 ± 23) ng/g in liver homogenate and 0.73 ± 0.06 and 0.54 ± 0.04 in cholangiocytes. The expression of P-STAT3 were 0.72 ± 0.04 and 0.58 ± 0.06 in cholangiocytes and cyclin D1 0.88 ± 0.04 and 0.74 ± 0.07 respectively. However, anti-sIL-6R inhibited the cholangiocytes proliferation and reduced the expressions of IL-6, STAT3 and cyclin D1. The DNA binding activity of STAT3 with cellular injury and the increases of serum ALP or GGT were also abrogated by the administration of anti-sIL-6R. With similar results, the RPM treatment had insignificant effects on the expression of IL-6 | ||
520 | |a CONCLUSION: The IL-6/STAT3 pathway initiates the cholangiocytes regeneration after liver transplantation so as to accelerate the biliary recovery. However RPM represses the cholangiocytes regeneration by inhibiting the STAT3 activation. It may have a negative effect on the healing and recovery of bile ducts in grafts with extended cold preservation | ||
650 | 4 | |a English Abstract | |
650 | 4 | |a Journal Article | |
650 | 7 | |a Interleukin-6 |2 NLM | |
650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
650 | 7 | |a Stat3 protein, rat |2 NLM | |
650 | 7 | |a Sirolimus |2 NLM | |
650 | 7 | |a W36ZG6FT64 |2 NLM | |
700 | 1 | |a Guo, Yi-bin |e verfasserin |4 aut | |
700 | 1 | |a Shi, Bing-yi |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Zhonghua yi xue za zhi |d 1994 |g 91(2011), 22 vom: 14. Juni, Seite 1523-8 |w (DE-627)NLM000566861 |x 0376-2491 |7 nnns |
773 | 1 | 8 | |g volume:91 |g year:2011 |g number:22 |g day:14 |g month:06 |g pages:1523-8 |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 91 |j 2011 |e 22 |b 14 |c 06 |h 1523-8 |