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as in immune-mediated events modeled by Con-A induced hepati-
tis (
96
). In rats receiving CCl
4
that causes severe liver fibrosis (in a
way modeling cirrhosis), IL-6 treatment before partial hepatec-
tomy had a protective effect associated with an increased survival
and STAT3 and AKT activation (
97, 98
). In the CCl
4
model, the
importance of IL-6 trans-signaling was also shown. Blocking IL-6
trans-signaling increased liver damage in this model (
99
). The
mechanism of IL-6 protection was also investigated. It was shown
that IL-6 inhibits oxidative tissue injury by inducing anti-oxidative
proteins including ref-1 and GPX1 (
100
). Many of the pro-survival,
anti apoptotic (Bcl2, Bcl-XL, survivin, and FLIP) and cell cycle
progression genes (cyclin A, cyclin D1-3, cyclin E, c-myc, cdc25A,
and c-fos; and downregulation of p21 and p27) are STAT3 targets.
The IL-6-gp130 signaling is, however, not tissue protective in all
tissues. In the skin, enhanced IL-6-gp130 signaling slows wound
healing due to hyperproliferation of keratinocytes (
101
).
8
Heart Regeneration: The Role of IL-6-gp130 Signaling
In recent years, the pivotal role of STAT3 signaling in the heart has
been explored. The role of STAT3 in tissue protection and regen-
eration has been reported (
102
). These effects were apparent
through specific gene regulation, prevention of injury, attenuated
under clinical risk conditions for coronary heart disease and reduc-
tion of reactive oxygen species (ROS). These effects include the
following: (1) The transcription factor Pim-1 was reported to be
essential for cardiac progenitor cell proliferation; in addition, this
factor is important in mediating myocardium contractility. Pim-1 is
regulated positively by STAT3 and AKT, which both lie down-
stream of IL-6-gp130 signaling. Recently, it has been shown that
Pim-1 is down-regulated in diabetic cardiomyopathy. The expres-
sion of Pim-1 in a diabetic heart improves cardiac function (
103
).
Although the role of the IL-6-gp130 pathway was not specifically
investigated, it is appealing to envision that Hyper-IL-6 could at
least induce the same protective effect. (2) It is becoming clear that
mammalians as well as fish hearts have the potential for cardiac
regeneration. In the Zebrafish, it was shown that the heart could
regenerate both following cryoinjury and coronary occlusion
(
104-106
). The mouse heart was also shown to be able to regener-
ate at the very early stages of the postnatal period (
107
). Based
on the role of STAT3 in heart regeneration, this effect could pos-
sibly induce both progenitor proliferation (0.25-1% of cardio-
myocytes) and mature cardiomyocytes (
108, 109
). In humans, it
has been recently estimated that about 1% of cardiomyocytes
proliferate during a one year period at the age of 25 years (
110
).
(3) In cardiomyocyte-restricted STAT3 knockout mice, STAT3
was demonstrated to be required for a preconditioned phenotype
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