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Involvement of the innate immune system in liver regeneration and injury

2006; Elsevier BV; Volume: 45; Issue: 3 Linguagem: Inglês

10.1016/j.jhep.2006.06.009

1600-0641

Nelson Fausto,

Liver Disease Diagnosis and Treatment

Recent research has shown that components of the innate immune system are intimately associated with liver disease and hepatic regeneration. It is well known that TNF plays a major role in alcoholic liver disease, and that cytokines such as Il-6, may contribute to fibrotic processes. More surprising, however, was the realization that some components of the innate immune system, including TNF and IL-6 may participate in the initiation of liver regeneration after partial hepatectomy [1Fausto N. Campbell J.S. Riehle K.J. Liver regeneration.Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1237) Google Scholar, 2Taub R. Liver regeneration: from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1239) Google Scholar, 3Diehl A.M. Cytokine regulation of liver injury and repair.Immunol Rev. 2000; 174: 160-171Crossref PubMed Scopus (265) Google Scholar]. The list of such components has grown since the original observations involving TNF, and now also includes lymphotoxins and proteins of the complement cascade [4Markiewski M.M. DeAngelis R.A. Lambris J.D. Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes?.Mol Immunol. 2006; 43: 45-56Crossref PubMed Scopus (88) Google Scholar, 5Anders R.A. Subudhi S.K. Wang J. Pfeffer K. Fu Y.X. Contribution of the lymphotoxin beta receptor to liver regeneration.J Immunol. 2005; 175: 1295-1300Crossref PubMed Scopus (59) Google Scholar, 6Akhurst B. Matthews V. Husk K. Smyth M.J. Abraham L.J. Yeoh G.C. Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury.Hepatology. 2005; 41: 327-335Crossref PubMed Scopus (92) Google Scholar]. As all of these agents can have toxic effects, their production and activation at the start of liver regeneration needs to be closely regulated. One of the main mechanisms for the control of the timing and extent of cytokine activation in the regenerating liver is through the activity of a family of proteins known as SOCS (Suppressors of Cytokine Synthesis). Of those, SOCS-3 has an important role in shutting off IL-6 and STAT-3 activation during liver regeneration [[7]Campbell J.S. Prichard L. Schaper F. Schmitz J. Stephenson-Famy A. Rosenfeld M.E. et al.Expression of suppressors of cytokine signaling during liver regeneration.J Clin Invest. 2001; 107: 1285-1292Crossref PubMed Scopus (137) Google Scholar]. Despite these major advances about the molecular mechanisms that initiate liver regeneration, there are still many important gaps. For instance, we do not know whether the participation of various components of the innate immune system is triggered by a single event or by multiple independent stimuli. One often suggested mechanism involves the activity of lipopolysaccharide (LPS), a chemical produced by the normal gram-negative intestinal flora. Despite the fact that data in the literature indicate that liver regeneration may be delayed in animals with a deficient response to LPS, in germ-free animals, and in animals treated with antibiotics to eliminate gram-negative gastrointestinal bacteria [[8]Cornell R.P. Liljequist B.L. Bartizal K.F. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice.Hepatology. 1990; 11: 916-922Crossref PubMed Scopus (134) Google Scholar], recent work using mice deficient for LPS receptors failed to confirm the participation of LPS in the initiation of liver regeneration [9Campbell J.S. Riehle K.J. Brooling J.T. Bauer R.L. Mitchell C. Fausto N. Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4.J Immunol. 2006; 176: 2522-2528PubMed Google Scholar, 10Seki E. Tsutsui H. Iimuro Y. Naka T. Son G. Akira S. et al.Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.Hepatology. 2005; 41: 443-450Crossref PubMed Scopus (145) Google Scholar]. However, these studies revealed that Myd 88, a key component of the signal transduction pathways activated by the Toll-like family of receptors that include the LPS receptor, may be required for cytokine production at the start of liver regeneration. Thus, a puzzling situation exists in which Myd 88, an intermediary molecule in Toll-like receptor pathways, appears to be necessary for cytokine activation in the regenerating liver, but neither the ligand nor the receptor involved in triggering the Myd 88 response has been identified. Other aspects of the cytokine involvement in liver regeneration that are not well understood include knowledge about the cellular circuitry involving hepatocytes and non-parenchymal cells required for cytokine production and regulation, and the interactions that may exist among various secreted cytokines. Furthermore, although TNF and IL-6 are most commonly studied in liver regeneration, other cytokines such as IL-12 and IL-15 are also likely to be involved. IL-15 is a particularly interesting pro-inflammatory cytokine in that its main effect in the lymphoid system is to stimulate the proliferation of NK (natural killer) and NKT (natural killer T cells) cells [11Bulfone-Paus S. Bulanova E. Budagian V. Paus R. The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling.Bioessays. 2006; 28: 362-377Crossref PubMed Scopus (58) Google Scholar, 12Fehniger T.A. Caligiuri M.A. Ontogeny and expansion of human natural killer cells: clinical implications.Int Rev Immunol. 2001; 20: 503-534Crossref PubMed Scopus (27) Google Scholar]. Both of these cells constitute most of the lymphoid cell population in human and mouse liver. NK cells are involved in innate immunity reactions against viruses and microbes, the first line of defense against these agents, and continue to be of interest as potential agents in cancer immunotherapy. NK-T cells are a subset of T cells that have NK markers [13Farag S.S. Fehniger T.A. Becknell B. Blaser B.W. Caligiuri M.A. New directions in natural killer cell-based immunotherapy of human cancer.Expert Opin Biol Ther. 2003; 3: 237-250Crossref PubMed Scopus (34) Google Scholar, 14Farag S.S. VanDeusen J.B. Fehniger T.A. Caligiuri M.A. Biology and clinical impact of human natural killer cells.Int J Hematol. 2003; 78: 7-17Crossref PubMed Scopus (83) Google Scholar]. A novel aspect of the role of these cells in the liver is their anti-fibrotic activity [15Radaeva S. Sun R. Jaruga B. Nguyen V.T. Tian Z. Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.Gastroenterology. 2006; 130: 435-452Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 16Melhem A. Muhanna N. Bishara A. Alvarez C.E. Ilan Y. Bishara T. et al.Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.J Hepatol. 2006; 45: 60-71Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar]. IL-15 has many overlapping effects with IL-2. The trimeric receptors for IL-2 and IL-15 have the same β and γ chains, but have a related but specific α chain that recognizes the appropriate ligand. There is general agreement that IL-15 and its receptor play an important role in the maintenance of the lymphoid cell populations in the liver [[17]Golden-Mason L. Kelly A.M. Doherty D.G. Traynor O. McEntee G. Kelly J. et al.Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development.Clin Exp Immunol. 2004; 138: 94-101Crossref PubMed Scopus (60) Google Scholar]. In addition, IL-15 has effects in other tissues, which may be related to, or independent of immune, responses. IL-15 protects against Fas and TNF-mediated apoptosis [11Bulfone-Paus S. Bulanova E. Budagian V. Paus R. The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling.Bioessays. 2006; 28: 362-377Crossref PubMed Scopus (58) Google Scholar, 18Bulfone-Paus S. Ungureanu D. Pohl T. Lindner G. Paus R. Ruckert R. et al.Interleukin-15 protects from lethal apoptosis in vivo.Nat Med. 1997; 3: 1124-1128Crossref PubMed Scopus (289) Google Scholar]. Probably through its effect on NK-T cells, it inhibits hepatic injury by concanavalin-A [[19]Li B. Sun R. Wei H. Gao B. Tian Z. Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism.Hepatology. 2006; 43: 1211-1219Crossref PubMed Scopus (52) Google Scholar], and the development of nephritis and apoptosis in the kidney [[20]Shinozaki M. Hirahashi J. Lebedeva T. Liew F.Y. Salant D.J. Maron R. et al.IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis.J Clin Invest. 2002; 109: 951-960Crossref PubMed Scopus (73) Google Scholar]. Moreover, IL-15 stimulates proliferation of many cell types [[11]Bulfone-Paus S. Bulanova E. Budagian V. Paus R. The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling.Bioessays. 2006; 28: 362-377Crossref PubMed Scopus (58) Google Scholar]. Blood levels of IL-15 increase in patients with chronic Hepatitis C Virus infection, and after IFN-α treatment [[21]Yamaji K. Nabeshima S. Murata M. Chong Y. Furusyo N. Ikematsu H. et al.Interferon-alpha/beta upregulate IL-15 expression in vitro and in vivo: analysis in human hepatocellular carcinoma cell lines and in chronic hepatitis C patients during interferon-alpha/beta treatment.Cancer Immunol Immunother. 2006; 55: 394-403Crossref PubMed Scopus (22) Google Scholar], suggesting that IL-15 is a component of the host anti-viral response. In ob/ob mice, leptin deficiency decreases hepatic IL-15 levels and reduces the number of NK cells [[22]Li Z. Lin H. Yang S. Diehl AM: murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system.Gastroenterology. 2002; 123: 1304-1310Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. However, there is some controversy about the role of IL-15 and NK/NK-T cells in liver regeneration. Several reports suggest that NK/NK-T cell activation may have a negative effect on liver regeneration [23Vujanovic N.L. Polimeno L. Azzarone A. Francavilla A. Chambers W.H. Starzl T.E. et al.Changes of liver-resident NK cells during liver regeneration in rats.J Immunol. 1995; 154: 6324-6338PubMed Google Scholar, 24Oishi K. Hayamizu K. Aihaiti X. Itamoto T. Arihiro K. Asahara T. G-CSF-induced evacuation of sinusoidal NK cells and the facilitation of liver regeneration in a partial hepatectomy.Cytokine. 2006; PubMed Google Scholar, 25Sun R. Gao B. Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma).Gastroenterology. 2004; 127: 1525-1539Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 26Ito H. Ando K. Nakayama T. Taniguchi M. Ezaki T. Saito K. et al.Role of Valpha 14 NKT cells in the development of impaired liver regeneration in vivo.Hepatology. 2003; 38: 1116-1124Crossref PubMed Scopus (62) Google Scholar], while other data suggest that NK-T cells increase in the regenerating liver and may participate in protective immunologic surveillance [[27]Minagawa M. Oya H. Yamamoto S. Shimizu T. Bannai M. Kawamura H. et al.Abo T: intensive expansion of natural killer T cells in the early phase of hepatocyte regeneration after partial hepatectomy in mice and its association with sympathetic nerve activation.Hepatology. 2000; 31: 907-915Crossref PubMed Scopus (109) Google Scholar]. Thus it is of great interest to determine whether IL-15 would modulate liver regeneration and hepatic injury. In this issue, Suzuki et al. [[28]Suzuki A. McCall S. Choi S.S. Sicklick J.K. Huang J. Qi Y. et al.Interleukin-15 increases hepatic regenerative activity.J Hepatol. 2006; 45: 410-418Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] report that IL-15 mRNA increases after partial hepatectomy, and in 3 models of chronic liver injury. Hepatocytes and oval cells in culture expressed IL-15 and its receptors, but exposure to IL-15 had no effect on the cells. However, in vivo administration of IL-15 caused 30% and 50% increases in the number of cells staining for cytokeratins, at 3 and 5 days after IL-15 injection, respectively. These results are particularly interesting because pancytokeratin staining is a marker for liver progenitor cells (oval cells), and also because the increase in oval cells 3 days after IL-15 injection apparently occurred in the absence of an inflammatory response. Given the lack of an effect of IL-15 on oval cell proliferation in culture, the results suggest that IL-15 may stimulate oval proliferation in intact livers indirectly, acting through another mediator. One potential candidate for this effect is TWEAK, a member of the TNF family of ligands, which was recently shown to cause oval cell proliferation in transgenic mice [[29]Jakubowski A. Ambrose C. Parr M. Lincecum J.M. Wang M.Z. Zheng T.S. et al.TWEAK induces liver progenitor cell proliferation.J Clin Invest. 2005; 115: 2330-2340Crossref PubMed Scopus (320) Google Scholar]. Suzuki et al. [[28]Suzuki A. McCall S. Choi S.S. Sicklick J.K. Huang J. Qi Y. et al.Interleukin-15 increases hepatic regenerative activity.J Hepatol. 2006; 45: 410-418Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] also reported that IL-15 injection caused some increases in hepatocyte proliferation and apoptosis. The mechanisms for these effects are difficult to sort out because hepatocyte proliferation and apoptosis took place 7 days after IL-15 injection, a time at which there was both oval cell proliferation and inflammation. Thus, it is uncertain whether hepatocyte replication is a secondary effect of cell injury, or a consequence of the IL-15 effect on oval cell proliferation. To further pursue the work and some of the important issues discussed by Suzuki et al. [[28]Suzuki A. McCall S. Choi S.S. Sicklick J.K. Huang J. Qi Y. et al.Interleukin-15 increases hepatic regenerative activity.J Hepatol. 2006; 45: 410-418Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar], it would be very informative to determine whether both IL-15 mRNA and the protein are increased in processes associated with progenitor cell proliferation in mouse and human liver. Detection of the protein is particularly important because the regulation of IL-15 expression is complex, and is often dependent on post-transcriptional and post-translational mechanisms. Moreover, IL-15 is anchored into the cell membrane, and its shedding is also under regulatory control [[11]Bulfone-Paus S. Bulanova E. Budagian V. Paus R. The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling.Bioessays. 2006; 28: 362-377Crossref PubMed Scopus (58) Google Scholar]. As indicated by Suzuki et al. [[28]Suzuki A. McCall S. Choi S.S. Sicklick J.K. Huang J. Qi Y. et al.Interleukin-15 increases hepatic regenerative activity.J Hepatol. 2006; 45: 410-418Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar], the potential differentiation of oval cells into hepatocytes after IL-15 injection merits further studies. Additional markers to identify oval cells need to be used to permit a more detailed analysis of the timing and extent of the oval cell effect, and whether IL-15 may increase both the proliferation and differentiation of oval cells. Finally, the role of IL-15 in liver regeneration remains unclear. In particular, it would be important to determine the timing of the expression of IL-15 mRNA and protein after partial hepatectomy, and identify the cells that express the cytokine during liver regeneration. Results from this work may finally resolve the controversies regarding the role of NK/NK-T cells in liver regeneration.