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Cited by 109Liver physiology and pathologyCytokine Signaling Pathways and InteractionsOrgan Transplantation Techniques and Outcomes

IL-22 is involved in liver regeneration after hepatectomy

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Ren, Xiaodan, Hu, Bin, Colletti, Lisa M.·2010·American Journal of Physiology-Gastrointestinal and Liver Physiology
DOI 10.1152/ajpgi.00075.2009PMC PMC2806105
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Abstract

Hepatocyte proliferation following partial hepatectomy is an important component of liver regeneration, and recent in vitro studies have shown that IL-22 is involved in cellular proliferation in a variety of cell types, including hepatocytes. IL-22 functions through IL-10Rβ and IL-22Rα. The goal of this study was to investigate the potential role of IL-22 in liver regeneration after 70% hepatectomy. Following 70% hepatectomy, done under general anesthesia in mice, serum IL-22 and hepatic IL-22Rα mRNA were significantly increased. Although administration of exogenous IL-22 prior to hepatectomy did not increase hepatocyte proliferation, administration of anti-IL-22 antibody before hepatectomy did significantly decrease hepatocyte proliferation. Furthermore, IL-22 treatment prior to 70% hepatectomy induced stat-3 activation; no significant changes were seen in ERK1/2 activation, stat-1 activation, or stat-5 activation. IL-22 pretreatment also significantly increased hepatic and serum IL-6 levels. In addition, animals treated with anti-IL-22 antibody also expressed less TGF-α. In conclusion, these data suggest that IL-22 is involved in liver regeneration and this may be due to interaction with IL-6 and TGF-α cascades.

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  • There is a significant increase in both IL-22 and its receptor (IL-22R) expression in the serum following 70% hepatectomy.

    “Studies have confirmed a significant increase in both IL-22 and its receptor (IL-22R) expression in the serum following 70% hepatectomy[48].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [48]

    The Results report a significant increase in serum IL-22 after 70% hepatectomy, but the increased IL-22Rα expression was measured as mRNA in the liver, not in serum. The claim incorrectly places both measurements in serum. (LLM, conf=0.93)

    Experimental — accuracy not yet measured

  • Interleukin-22 (IL-22) is a critical regulator of liver regeneration following partial hepatectomy.

    “Another critical regulator of LR following PH is Interleukin-22 (IL-22).”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [48]

    The Discussion reports that blocking IL-22 significantly reduced hepatocyte proliferation after 70% hepatectomy, supporting a role in liver regeneration. But it describes IL-22 as at least partially responsible, and the Results found no significant proliferation increase with added IL-22. Calling it a “critical regulator” states the role more strongly than the paper does. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • IL-22, through its interaction with IL-6, TGF-β, and STAT3, plays a crucial role in hepatocyte proliferation and liver recovery.

    “IL-22, through its interaction with IL-6, TGF-β, and STAT3, plays a crucial role in hepatocyte proliferation and liver recovery.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [48]

    The Abstract and Discussion report that IL-22 is involved in hepatocyte proliferation and liver regeneration after 70% hepatectomy, with evidence involving IL-6 and STAT3. The growth factor studied is TGF-α, not TGF-β, so the claimed interaction with TGF-β is unsupported by this paper. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • IL-22 administration increases IL-6 and TGF-β levels, indicating that its regenerative effects are closely linked to these signaling pathways.

    “Conversely, IL-22 administration increases IL-6 and TGF-β levels, indicating that its regenerative effects are closely linked to these signaling pathways.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [48]

    The Discussion reports that IL-22 administration increased hepatic and serum IL-6. It reports decreased TGF-α after IL-22 blockade, not increased TGF-β after administration; the claimed link to TGF-β is therefore unsupported. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Blocking IL-22 slows down liver regeneration, as evidenced by a decrease in DNA synthesis (reduced BrdU incorporation) and lower activation of STAT3.

    “Blocking IL-22 has been shown to slow down LR, as evidenced by a decrease in DNA synthesis (reduced BrdU incorporation) and lower activation of signal transducer and activator of transcription 3 (STAT3), a key transcription factor involved in cell survival and proliferation.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [48]

    The Discussion (page unavailable) reports delayed liver regeneration and reduced BrdU staining after IL-22 blockade. Although an earlier Discussion passage says blockade reduced STAT3 activation, the Results explicitly report no effect, as does the Discussion’s concluding account. The claim’s lower-STAT3-activation component is therefore not supported by the reported results. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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References 30 · Cited by 109

Research works printed but not linked: 26

  1. [1]Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL. Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res 21: 1047–1053, 2001 [DOI] [PubMed] [Google Scholar]
  2. [2]Akhurst B, Matthews V, Husk K, Smyth MJ, Abraham LJ, Yeoh GC. Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury. Hepatology 41: 327–335, 2005 [DOI] [PubMed] [Google Scholar]
  3. [4]Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 174: 3695–3702, 2005 [DOI] [PubMed] [Google Scholar]
  4. [5]Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, Diepolder H, Marquardt A, Jagla W, Popp A, Leclair S, Herrmann K, Seiderer J, Ochsenkuhn T, Goke B, Auernhammer CJ, Dambacher J. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 290: G827–G838, 2006 [DOI] [PubMed] [Google Scholar]
  5. [6]Brand S, Dambacher J, Beigel F, Zitzmann K, Heeg MH, Weiss TS, Prufer T, Olszak T, Steib CJ, Storr M, Goke B, Diepolder H, Bilzer M, Thasler WE, Auernhammer CJ. IL-22 mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am J Physiol Gastrointest Liver Physiol 292: G1019–G1028, 2007 [DOI] [PubMed] [Google Scholar]
  6. [7]Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res 16: 902–907, 2006 [DOI] [PubMed] [Google Scholar]
  7. [9]Gallucci RM, Simeonova PP, Toriumi W, Luster MI. TNF-alpha regulates transforming growth factor-alpha expression in regenerating murine liver and isolated hepatocytes. J Immunol 164: 872–878, 2000 [DOI] [PubMed] [Google Scholar]
  8. [10]Gurney AL. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int Immunopharmacol 4: 669–677, 2004 [DOI] [PubMed] [Google Scholar]
  9. [11]Kawamura H, Govindarajan S, Aswad F, Machida K, Lai MM, Sung VM, Dennert G. HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice. Hepatology 44: 936–944, 2006 [DOI] [PubMed] [Google Scholar]
  10. [12]Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg 197: 634–659, 2003 [DOI] [PubMed] [Google Scholar]
  11. [13]Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem 276: 2725–2732, 2001 [DOI] [PubMed] [Google Scholar]
  12. [14]Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem 277: 33676–33682, 2002 [DOI] [PubMed] [Google Scholar]
  13. [15]Liao SC, Cheng YC, Wang YC, Wang CW, Yang SM, Yu CK, Shieh CC, Cheng KC, Lee MF, Chiang SR, Shieh JM, Chang MS. IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173: 6712–6718, 2004 [DOI] [PubMed] [Google Scholar]
  14. [17]Radaeva S, Sun R, Pan HN, Hong F, Gao B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39: 1332–1342, 2004 [DOI] [PubMed] [Google Scholar]
  15. [18]Ren X, Carpenter A, Hogaboam C, Colletti L. Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse. Am J Pathol 163: 563–570, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [19]Ren X, Hogaboam C, Carpenter A, Colletti L. Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy. J Clin Invest 112: 1407–1418, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [20]Ren X, Hu B, Colletti L. Stem cell factor and its receptor, c-kit, are important for hepatocyte proliferation in wild-type and tumor necrosis factor receptor-1 knockout mice after 70% hepatectomy. Surgery 143: 790–802, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [21]Sanchez A, Nagy P, Thorgeirsson SS. STAT-3 activity in chemically-induced hepatocellular carcinoma. Eur J Cancer 39: 2093–2098, 2003 [DOI] [PubMed] [Google Scholar]
  19. [22]Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol 168: 5397–5402, 2002 [DOI] [PubMed] [Google Scholar]
  20. [23]Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity 21: 241–254, 2004 [DOI] [PubMed] [Google Scholar]
  21. [24]Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, Volk HD, Sterry W, Sabat R. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 36: 1309–1323, 2006 [DOI] [PubMed] [Google Scholar]
  22. [25]Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2–4 and IL-22R. J Biol Chem 275: 31335–31339, 2000 [DOI] [PubMed] [Google Scholar]
  23. [26]Xu J, Keeton AB, Franklin JL, Li X, Venable DY, Frank SJ, Messina JL. Insulin enhances growth hormone induction of the MEK/ERK signaling pathway. J Biol Chem 281: 982–992, 2006 [DOI] [PubMed] [Google Scholar]
  24. [27]Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, Chen Z, Dillon SR, Gao Z, Gilbert T, Madden K, Schlutsmeyer S, Yao L, Whitmore TE, Chandrasekher Y, Grant FJ, Maurer M, Jelinek L, Storey H, Brender T, Hammond A, Topouzis S, Clegg CH, Foster DC. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc Natl Acad Sci USA 98: 9511–9516, 2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [29]Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27: 647–659, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. [30]Zimmers TA, McKillop IH, Pierce RH, Yoo JY, Koniaris LG. Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology 38: 326–334, 2003 [DOI] [PubMed] [Google Scholar]

Authors
Ren, X., Hu, B., & Colletti, L. M.
Affiliations
University of Michigan (US)
Corresponding author
Colletti, Lisa M.
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Published
2010-01
Volume
298
Issue
1
Pages
G74-G80
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
DOI
10.1152/ajpgi.00075.2009
PMC
PMC2806105
OpenAlex
W2147833105
Cited by
109
References
30
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 12 · 2016: 11 · 2015: 11 · 2014: 10 · 2013: 10 · 2012: 7
FWCI
3.89
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (1R01 DK58106, R01DK053224, R01DK058106, 1R01DK53224)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
IL-22, liver regeneration, partial hepatectomy, hepatocyte proliferation, STAT3 signaling, interleukin-6, transforming growth factor-alpha, ERK1/2, STAT1, STAT5
MeSH terms
Interleukin-22, Animals, Cell Division, Female, Hepatectomy, Interleukins, Liver, Liver Regeneration, Mice, Inbred C57BL, Phosphorylation, Recombinant Proteins, RNA, Messenger, Interleukin-6, Up-Regulation, Transforming Growth Factor alpha, Hepatocyte Growth Factor, Receptors, Interleukin, MAP Kinase Signaling System, Hepatocytes, Extracellular Signal-Regulated MAP Kinases, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Mice

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