Special To BioWorld Today
How is a liver like a paramecium? Doctors have long recognized thatthe liver, like the paramecium, can regenerate masses of cells thathave been cut away.
Yet how the liver accomplishes this remarkable feat of renewal hasremained a scientific mystery, until now. Researchers at theUniversity of Pennsylvania and at Merck & Co.'s Institute forResearch in Molecular Biology, in Bologna, Italy, reported in theNov. 22 Science that the growth factor interleukin-6 (IL-6) mediatesliver repair.
The researchers said that the finding may have profound practicalimplications. IL-6 may someday improve recovery from livertransplantation and yield new treatments for people who haveingested poisons. Ultimately, it may help researchers understand anddevelop treatments for the liver damage that occurs in people withcirrhosis and chronic hepatitis.
The discovery also sheds new light on the scope of the role IL-6plays in tissue growth. Although prior research has demonstrated thatIL-6 can promote the proliferation of bone, blood and immune cells,this research is the first to demonstrate that IL-6 plays an importantrole in liver regeneration. Conversely, blocking the action of IL-6may interfere with liver recovery.
The researchers carried out their experiments using knock-out mice,which were deprived of the gene that produces IL-6. When sectionsof their livers were cut away, the mice began to deteriorate. Most ofthem died; some grew so ill that they had to be sacrificed.
But one dose of IL-6 prior to surgery enabled knock-out mice tosurvive the loss of large portions of their livers and regenerate thelost tissue, said Rebecca Taub, of the University of PennsylvaniaSchool of Medicine in Philadelphia.
"The cells in the remnant of the liver rapidly replicate, and the liver isreconstituted in a few days," Taub told BioWorld Today. "It doesn'treconstitute in the lobes you took out; the structure doesn't lookexactly the same; but the mass is the same." More importantly, theknock-out mice remained as healthy as normal mice with intact livers.
The liver is crucial because it is the body's first line of defenseagainst ingested toxins. When a nutrient or a toxin enters thebloodstream, it goes directly to the liver. Sugars are converted intoglycogen, which is taken up into cells and converted into energy.Toxins are cleared from the body, but at a cost. Liver cells, calledhepatocytes, when subjected to this kind of toxic assault, rapidly dieoff. To survive, the liver must replace these cells. "The cells thatremain regenerate, a process that is unique to the liver," Taub said.
That's where IL-6 comes in. Earlier studies by Taub and hercolleagues have shown that concentrations of certain transcriptionfactors, proteins that attach to DNA to activate genes, quickly rise asthe liver regenerates. High concentrations of these factors can bemeasured within moments after liver damage occurs. Subsequentexperiments demonstrated that many of the genes activated by thisprocess are not active in healthy livers. One of the trauma-inducedtranscription factors, STAT3, activates the IL-6 gene.
Taub and her coworkers suspected that the newly active genesproduce proteins that are involved in the liver's repair effort. Theypostulated that IL-6 _ which appears to be secreted by the whiteblood cells, called macrophages, or by cells lining the blood vesselsthemselves _ may be particularly important. Hence, the experimentsin mice lacking the IL-6 gene.
"Treatment of IL-6 deficient mice with a single preoperative dose ofIL-6 returned STAT3 binding, gene expression, and hepatocyteproliferation to near normal and prevented liver damage, establishingthat IL-6 is a critical component of the regenerative response," theresearchers reported in Science.
A dose of IL-6 before a liver transplant, therefore, might help assurethe graft's survival despite the immune onslaught known as graft-vs.-host disease. It may also help repair livers damaged by ingestion ofsuch substances as the over-the-counter pain reliever acetaminophen,which can be extremely toxic if too much is taken, or carbontetrachloride, a poisonous component of fire extinguishers which wasformerly used as a cleaning fluid. What the researchers do not yetknow is whether it will perform as dramatically in humans.
They also do not know whether a dose of IL-6 will help peoplesuffering from alcoholism or chronic hepatitis. In these diseases, theliver gradually deteriorates despite its efforts to repair itself. Oneconsequence of this thwarted repair process is the build-up of scartissue, which performs no metabolic function.
IL-6 seems to play a role in this process, but the nature of its role isnot yet understood, Taub said. Studies have shown that peoplesuffering from alcoholism or chronic hepatitis have sustainedelevations of IL-6 in their blood. The reason for this is unknown. "Itis not clear whether IL-6 is just helping regeneration or helping thecells to create scar tissue," Taub said. It may be that the othercytokines, IL-1 and TNF-a, also are involved, and that scarringoccurs when a chronic, toxic assault disturbs the "precise balance" ofthe three growth factors, she said.
The researchers plan to examine this question by studying mousemodels of chronic liver damage. Steady doses of carbon tetrachloridealone, or of carbon tetrachloride mixed with Phenobarbital, promotescarring that closely mimics the faulty repair seen in the livers ofchronic alcoholics. "The goal is to create a situation that lookshistologically similar to chronic alcoholism," Taub said, "and animalsdon't like to drink alcohol."
Taub's team plans to subject knock-out mice and normal mice to thisordeal, then treat both groups of liver-damaged rodents with IL-6.The group wants to see whether IL-6 prompts their livers toregenerate without scarring. n
-- Steve Sternberg
(c) 1997 American Health Consultants. All rights reserved.