<title>1. INTRODUCTION</title> <p>Peroxisome proliferator-activated receptor-gamma (PPAR<italic>γ</italic>, NR1C3) has been described as a master
regulator of adipocytes differentiation [##REF##10447513##1##]; and since the discovery
that the insulin-sensitizing thiazolidinedione drugs are PPAR<italic>γ</italic> agonists [##REF##7768881##2##], the role of this receptor
in adipogenesis has been studied in detail. PPAR<italic>γ</italic> is also abundant in the gastrointestinal tract,
where it is highly expressed in epithelial cells [##REF##9228052##3##, ##REF##9065481##4##]. High-level expression of
PPAR<italic>γ</italic> in the gut epithelium suggests some important physiological
role in the gut, although this role is not well understood. From the standpoint
of pathology, PPAR<italic>γ</italic> has been implicated in both transformation and
inflammation in the gut. However, there are conflicting data concerning the
efficacy and even the safety of PPAR<italic>γ</italic> agonists in clinical management of
gastrointestinal cancer and inflammation. We will undertake in this review to
summarize both historical and recent data that relate to three questions: What
is the physiological role of PPAR<italic>γ</italic> in gastrointestinal epithelial cells? Is PPAR<italic>γ</italic> a colon cancer suppressor? And what is the
role of PPAR<italic>γ</italic> in inflammation?</p>
<p>Recommended by Dipak Panigrahy</p> <p>Although the highest levels of PPAR<italic>γ</italic> expression in the body have been reported in the gastrointestinal epithelium, little is known about the physiological functions of that receptor in the gut. Moreover, there is considerable controversy concerning the effects of thiazolidinedione PPAR<italic>γ</italic> agonists on the two major diseases of the gastrointestinal track: colorectal cancer and inflammatory bowel disease. We will undertake to review both historical and recently published data with a view toward summarizing what is presently known about the roles of PPAR<italic>γ</italic> in both physiological and pathological processes in the gastrointestinal epithelium.</p>
<title>2. THE PHYSIOLOGICAL ROLE OF PPAR<italic>γ</italic> IN
GASTROINTESTINAL EPITHELIAL CELLS</title> <p>PPAR<italic>γ</italic> is expressed in epithelial cells of both the
large and small intestines [##REF##9228052##3##, ##REF##9065481##4##]. Relatively lower levels of expression are observed in the small intestine, which appears to express PPAR<italic>γ</italic> at more or less uniform abundance from the
duodenum to the caecum [##REF##17519361##5##]. Very high levels of PPAR<italic>γ</italic> are expressed in the proximal colon, with
somewhat lower levels observed in the mid and distal colon [##REF##17519361##5##, ##REF##10467224##6##]. The highest levels of PPAR<italic>γ</italic> in the body are observed in highly
differentiated lumenal epithelial cells of the proximal colon. It has also been
observed that PPAR<italic>γ</italic> is induced when Caco2 cells undergo
differentiation in culture [##REF##10467224##6##], leading to the suggestion
that induction of PPAR<italic>γ</italic> is associated with differentiation of colonic
epithelial cells. However, a careful analysis of PPAR<italic>γ</italic> expression in the colon suggests that this
conclusion is correct only within a limited context [##REF##17519361##5##]. Basal epithelial cells of
proximal crypts are highly differentiated, yet express significantly lower
levels of PPAR<italic>γ</italic> than lumenal epithelial cells from the same
crypts. Furthermore, PPAR<italic>γ</italic> expression in the distal colon is more or less
uniform throughout the crypts, with slightly higher levels of expression
observed in the less differentiated basal crypt cells, rather than the more
highly differentiated lumenal epithelial cells [##REF##17519361##5##, ##REF##12557160##7##]. Thus, it is not generally
the case that induction of PPAR<italic>γ</italic> is associated with differentiation of colonic
epithelial cells. It is, however, the case that all colonic epithelial cells
express significant levels of PPAR<italic>γ</italic>. This is an important point, since some of the
effects of PPAR<italic>γ</italic> are manifest in the transit amplifying cells
that support renewal of the colonic epithelium. Whether PPAR<italic>γ</italic> is expressed in colonic stem cells remains an
open question.</p> <p>A
significantly different pattern of PPAR<italic>γ</italic> expression is observed in the epithelium of
the small intestine. Transit amplifying cells within the crypts of Lieberkühn
express little or no PPAR<italic>γ</italic> [##REF##16574311##8##, ##REF##17565986##9##]. Instead, this receptor is
induced at the crypt/villus junction, where small intestinal epithelial cells
undergo differentiation into mature villus epithelial cells. Thus, in the small
intestine it is unambiguously the case that induction of PPAR<italic>γ</italic> is associated with differentiated function,
and it has been reported that PPAR<italic>γ</italic> collaborates with Hic5 to promote
differentiation of embryonic small intestinal epithelial cells [##REF##15687259##10##].</p> <p>Efforts
to understand the role of PPAR<italic>γ</italic> in differentiated function of gut epithelial
cells have been hindered by the lack of good cellular models to study the
mechanisms of action of PPAR<italic>γ</italic> in culture. There are no nontransformed
colonic epithelial cell lines, and primary colonic epithelial cells have proved
to be difficult, if not impossible, to maintain in culture for even a few
hours. There are several nontransformed epithelial cell lines derived from the
rat embryonic small bowel (e.g., RIE1
and IEC6), but these cells are derived from proliferative crypt cells and, like
the transit amplifying cells from which they were derived, these cells express
no PPAR<italic>γ</italic>. It has been possible to engineer RIE1 cells
to express PPAR<italic>γ</italic>, thereby modeling the transition that occurs
at the crypt/villus junction [##REF##16574311##8##, ##REF##16815847##11##]. Activation of PPAR<italic>γ</italic> in such cells results in irreversible
withdrawal form the cell cycle, promotes motility, and reduces cellular
adhesion.</p> <p>Genomic
profiling indicates that PPAR<italic>γ</italic> targets in such cells fall into four major functional
cohorts [##REF##16574311##8##]. The largest of these
cohorts consists of genes that are involved in metabolism, and a large
proportion of lipid transport and metabolism genes are evidenced within this
group. This observation is consistent with our understanding of the metabolic
role of PPAR<italic>γ</italic> in other tissues [##REF##7926726##12##–##REF##7799943##16##]. A second cohort of PPAR<italic>γ</italic> target genes was ontologically linked to
signal transduction. The data suggest that there is extensive crosstalk between
PPAR<italic>γ</italic> and other signaling pathways within intestinal
epithelial cells. A third cohort of genes was linked to proliferation,
consistent with the observation that activation of PPAR<italic>γ</italic> within these cells results in inhibition of
culture growth and irreversible withdrawal from the cell cycle. Somewhat
surprisingly, the forth functional cohort of PPAR<italic>γ</italic> target genes was ontologically linked to
cellular motility and adhesion. Such processes have not been generally thought
of as linked to activation of nuclear receptors. Nevertheless, activation of
PPAR<italic>γ</italic> in intestinal epithelial cells potently
induces cellular motility, through a mechanism that involves Rho family GTPases
and MAPK activation [##REF##16815847##11##]. Renewal of the intestinal
epithelium is tightly coupled to migration of differentiated epithelial cells
from the crypts to the villus tips, and the observation that PPAR<italic>γ</italic> regulates intestinal epithelial cell motility
provides a very important clue into the potential physiological role of this
receptor in the gastrointestinal epithelium.</p> <p>Genomic
analysis of PPAR<italic>γ</italic>
targets in colonic epithelial cells isolated from thiazolidinedione-treated
mice indicates that, in general, similar processes are regulated in epithelial
cells from the colon and small intestine [##REF##17519361##5##]. Major ontological cohorts
were identified that link PPAR<italic>γ</italic> activation to metabolism, signal transduction,
and migration/motility. In contrast to the results obtained with intestinal
epithelial cells in culture, no proliferative cohort of PPAR<italic>γ</italic> target genes was identified in colonic
epithelial cells isolated from thiazolidinedione-treated mice. This result was
unanticipated since such drugs significantly inhibit BrdU incorporation into
both proximal and distal colonic epithelial cells. Failure to detect a cohort
of proliferation-related PPAR<italic>γ</italic> target genes in vivo is probably attributable to the fact that only a small
subpopulation of cells is involved in proliferation in the colonic epithelium,
such that the contribution of RNA from such cells is diluted by the much larger
postmitotic population. Genomic studies of this sort are, therefore, useful for
analysis of PPAR<italic>γ</italic> effect on the differentiated, postmitotic
epithelial cells; but such studies are unlikely to reveal much information
about the effects of PPAR<italic>γ</italic> on proliferative colonic epithelial cells,
which are presumably the targets for transformation.</p> <p>PPAR<italic>γ</italic> expression and distribution are very different
in the proximal and distal colonic epithelium, implying that this receptor may
have different functions in the proximal and distal colon. Genomic analysis
indicates that the majority of PPAR<italic>γ</italic> target genes are expressed in both proximal
and distal epithelial cells [##REF##17519361##5##], suggesting that there is
substantial overlap between the physiological functions of PPAR<italic>γ</italic> in these tissues. However, a subset of PPAR<italic>γ</italic> target genes is restricted to the proximal
colon, and a second subset is expressed predominantly in the distal colon.
Intriguingly, the proximal PPAR<italic>γ</italic> target genes are all induced by
thiazolidinediones, whereas the distal target genes are all repressed. The
significance of this observation is unknown at this time. However, the
observation that PPAR<italic>γ</italic> represses genes that are differentially
expressed in the distal colon is consistent with the hypothesis that PPAR<italic>γ</italic> may suppress differentiated function in that
tissue. This hypothesis tends to contradict a large number of observations to
the effect that PPAR<italic>γ</italic> promotes differentiated function, and
additional studies are needed to confirm this unanticipated observation.</p> <p>In
summary, the lack of appropriate cellular models to study the mechanism of
action of PPAR<italic>γ</italic> in nontransformed gut epithelial cells
has significantly impaired our ability to understand the role of this receptor
in gut physiology. Nevertheless, genomic analyses of genetically engineered
intestinal epithelial cells and colonic epithelial cells isolated from
thiazolidinedione-treated mice have provided important clues. The data suggest
that PPAR<italic>γ</italic> is a potent metabolic regulator in gut
epithelial cells. This suggestion is obviously consistent with what we know
about PPAR<italic>γ</italic> in mesenchymal cells. There is a strong
suggestion that PPAR<italic>γ</italic> is involved in extensive crosstalk with other
signal transduction pathways, suggesting that this receptor plays an important
role in integrating the physiological response to a wide variety of
extracellular signals in vivo.
Finally, both genomic and cellular data indicate that PPAR<italic>γ</italic> plays a very important role in regulating
cellular motility, which is one of the major differentiated functions of
intestinal epithelial cells. The challenge at this time is to put the
information we have into a physiological context and to use these data to
understand the role of PPAR<italic>γ</italic> in malignant transformation of
gastrointestinal epithelial cells.</p> <title>3. PPAR<italic>γ</italic> AS A COLON CANCER SUPPRESSOR</title> <p>The evidence in support of PPAR<italic>γ</italic> as a colon cancer suppressor is based upon a
relatively small number of observations, and not all of these observations are
consistent with each other. The most compelling data come from studies using
the azoxymethane (AOM)-treated rodent model, which has been widely studied as a
model of sporadic colon carcinogenesis. Two initial studies in AOM-treated rats
used troglitazone, a relatively weak PPAR<italic>γ</italic> agonist [##REF##11346461##17##, ##REF##11289109##18##]. The endpoint in these
experiments was aberrant crypt foci (ACF), rather than colon tumors.
Nevertheless, both of these studies indicated that troglitazone potently inhibits
ACF formation, thereby presumably reducing the risk of subsequent tumor
formation in rats. It was subsequently shown that troglitazone, pioglitazone,
and rosiglitazone inhibit ACF formation in AOM-treated Balb/c mice [##REF##12557142##19##]. This was the first study
that demonstrated that thiazolidinediones inhibit colon tumor formation, in
addition to ACF formation, in the AOM model of colon carcinogenesis. This
observation was consistent with the report that whole animal hemizygous
knockout of PPAR<italic>γ</italic> suppressed AOM-mediated colon tumor formation
in mice [##REF##12557160##7##]. It has subsequently been
reported that RS5444, a very high-affinity third generation thiazolidinedione,
inhibits ACF formation and blocks tumor formation in AOM-treated C57BL/6 mice [##REF##17519361##5##, ##REF##18546290##20##]. Overall, these data
unambiguously indicate that PPAR<italic>γ</italic> inhibits some very early step in
transformation of colonic epithelial cells in AOM-treated rodents.</p> <p>In
contrast to the data cited above, two reports have concluded that
thiazolidinediones induce caecal tumors in mice [##REF##15818612##21##, ##REF##14713549##22##]. These reports have not been
independently confirmed, and other investigators have not observed such an
effect. However, this may reflect the fact that caecal tumors were observed
only in mice that had received very high concentrations of thiazolidinediones
for very long periods of time [##REF##15818612##21##, ##REF##14713549##22##]. The pathological
significance of these observations is unclear at this time. Caecal tumors are
very rare in both mice and humans, and the concentrations of thiazolidinediones
that were used in these experiments were very likely far beyond any dose that
would be tolerated in humans, in which peripheral edema is the dose limiting
response to such drugs. Nevertheless, the potential significance of these
disturbing observations warrants additional consideration.</p> <p>The
major controversy in the PPAR<italic>γ</italic> field has revolved around two high-profile
papers that reported increased colon tumor formation in APC<sup>+/Min</sup> mice treated with thiazolidinediones [##UREF##0##23##, ##UREF##1##24##]. One of these papers
reported a significant increase in colon tumor size in APC<sup>+/Min</sup> mice
treated with either troglitazone or rosiglitazone. The companion paper reported
a slight, but significant, increase in the number of colon tumors in APC<sup>+/Min</sup> mice treated with troglitazone. No increase in tumor size was observed in the
second report, which was, therefore, not entirely consistent with the first.
Moreover, two subsequent reports failed to reproduce the effect of
thiazolidinediones in APC<sup>+/Δ1309</sup> or APC<sup>+/Min</sup> mice [##REF##14522940##25##, ##REF##14611672##26##]. It was also reported that
whole animal hemizygous knockout of PPAR<italic>γ</italic> had no affect on tumor number or size in APC<sup>+/Min</sup> mice [##REF##12557160##7##], an observation that is at
variance with the notion that PPAR<italic>γ</italic> promotes tumor formation in mice that contain
activating germ line mutations in the Wnt/APC/<italic>β</italic>-catenin pathway. It has recently been reported
that biallelic knockout of PPAR<italic>γ</italic> in colonic epithelial cells promotes tumor
formation in APC<sup>+/Min</sup> mice [##REF##16858678##27##], indicating that PPAR<italic>γ</italic> is, in fact, acting to suppress tumor
formation in the 
Min mouse. On the whole, the evidence
no longer supports the hypothesis that activation of PPAR<italic>γ</italic> promotes tumor formation in mice with germ
line APC mutations.</p> <p>A
recent report describes the effects of PPAR<italic>γ</italic> agonists in pre-established tumors in
AOM-treated mice [##REF##18546290##20##]. Such tumors invariably
contain somatic mutations that activate the Wnt/APC/<italic>β</italic>-catenin signaling pathway [##REF##10836998##28##]. Thiazolinedinediones had no
effect on growth or incidence of colon tumors when the drug was given after
tumor formation had occurred [##REF##18546290##20##]. However, activation of PPAR<italic>γ</italic> under these circumstances had a profound
inhibitory effect on tumor progression. This effect was most strikingly
apparent in the development of carcinoma in
situ, which was detected in about 1/3 of the control tumors but was
never observed in thiazolidinedione-treated tumors. Since formation of
carcinoma in situ involves invasion of the surrounding stoma, it is tempting to
speculate that this observation indicates that PPAR<italic>γ</italic> inhibits invasion in vivo, consistent with several reports that indicate that
invasion by human colon cancer cell lines in culture is inhibited by PPAR<italic>γ</italic> [##REF##17565986##9##, ##REF##15289864##29##]. Notably, activation of PPAR<italic>γ</italic> in pre-established tumors had no significant
effect on BrdU incorporation, consistent with the lack of any significant
effect on tumor size. This observation is at variance with several reports that
thiazolidinediones inhibit proliferation of human colon cancer cell lines in
culture and in xenografts [##REF##17565986##9##, ##REF##15289864##29##–##REF##11950812##35##]. The significance of this
discrepancy requires additional investigation, but the data are consistent with
the hypothesis that the suppressive effects of PPAR<italic>γ</italic> on established tumors may be due to inhibition
of tumor progression, rather than inhibition of tumor growth.</p> <p>On
balance, the data seem unambiguously clear in one respect: PPAR<italic>γ</italic> suppresses colon carcinogenesis in mice. The
primary effect appears to be inhibition of some early stage in transformation.
The ability of PPAR<italic>γ</italic> to block early stage transformation is
presumably due to some effect on normal colonic epithelial cells, which
emphasizes the importance of understanding the functions of this receptor in
the normal colonic epithelium. It is also clear that whereas PPAR<italic>γ</italic> inhibits proliferation of normal intestinal
epithelial cells, this response is attenuated early in transformation. Although
the antiproliferative effects of PPAR<italic>γ</italic> appear to be lost in cells that have either
germ line or somatic mutations in <italic>β</italic>-catenin signaling, the data indicate that this
receptor still retains the ability to inhibit tumor progression, at least in
AOM-induced tumors. Finally, we submit that there is very little solid evidence
that PPAR<italic>γ</italic> promotes colon carcinogenesis under any
pharmacologically relevant conditions.</p> <p>The
role of PPAR<italic>γ</italic> as a suppressor of colon carcinogenesis in
rodents is beyond question, but the evidence that PPAR<italic>γ</italic> is a colon cancer suppressor in humans is not
so compelling. Although an early report indicated that loss-of-function
mutations in PPAR<italic>γ</italic> were common in colon cancer [##REF##10394368##36##], this claim has not
subsequently been confirmed [##REF##11431375##37##]. It has been reported that a
polymorphism in codon 12 of PPAR<italic>γ</italic> is associated with colon cancer risk [##REF##11956653##38##]. However, this polymorphism
is manifest in PPAR<italic>γ</italic>2, which is expressed at relatively low levels
in the colonic epithelium [##REF##9228052##3##, ##REF##9065481##4##], and not in the major
colonic PPAR<italic>γ</italic> isoform, PPAR<italic>γ</italic>1 which differs in N-terminal sequence from
PPAR<italic>γ</italic>2. PPAR<italic>γ</italic> expression is reduced in ulcerative colitis [##REF##12730867##39##] and acromegaly [##REF##11994396##40##], two conditions that
predispose to colon cancer; and one might extrapolate from data with hemizygous
knockout mice [##REF##12370429##41##] to postulate that a
reduction in PPAR<italic>γ</italic> expression increases the likelihood of
transformation in the human colon. However, the evidence in support of such a
conclusion is not very strong. Finally, a small phase II trial in which
troglitazone was used to treat patients with late stage metastatic colon cancer
produced no objective response [##UREF##3##42##]. One might argue that lack
of response in this case was due to the rather low potency of the agonist or
the very advanced stage of cancer in these patients. Alternatively, one might
point to the data in mice, which indicate that PPAR<italic>γ</italic> has little or no effect on growth of
established colon tumors in AOM-treated mice [##REF##18546290##20##].</p> <p>The
best evidence for a tumor suppressive role of PPAR<italic>γ</italic> in humans comes from studies of established
human colon cancer cell lines [##REF##17565986##9##, ##REF##15289864##29##–##REF##12269390##31##, ##REF##10076568##33##–##REF##11950812##35##, ##REF##12591919##43##]. Some of these cells exhibit
growth arrest in culture when treated with thiazolidinediones, and growth of
colon cancer xenografts has also been observed in thiazolidinedione-treated
mice. However, many (in our experience most) human colon cancer cell lines are
resistant to growth inhibition by concentrations of thiazolidinediones that are
sufficient to maximally activate PPAR<italic>γ</italic>. Such observations raise two important
questions: why are some colon cancer cell lines resistant to PPAR<italic>γ</italic> agonists? And to what extent are the effects
of thiazolidinediones dependent upon PPAR<italic>γ</italic> expression and/or activity? Both of these
questions are significant in terms of the use of thiazolidinediones as
chemotherapeutic agents in colon cancer.</p> <p>The
most compelling case for pharmacological application of PPAR<italic>γ</italic> agonists in colon cancer is as a preventive
agent. Clearly, PPAR<italic>γ</italic> is preventive in mouse models of sporadic
colon cancer. However, the legal climate in USA at this time does not favor the
development of chemopreventive drugs, particularly those that may have
cardiovascular side effects [##REF##17517853##44##]. These considerations do not
preclude a prophylactic use for PPAR<italic>γ</italic> agonists. Patients with large numbers of ACF
are at increased risk for development of subsequent colon cancers [##REF##9260708##45##–##REF##12397272##47##], and it is plausible that
short-term treatment with PPAR<italic>γ</italic> agonists might result in a decrease in ACFs
and a subsequent reduction in colon cancer risk. From a clinical standpoint, it
is therefore important to ascertain if activation of PPAR<italic>γ</italic> in humans suppresses ACF formation, as has
been observed in AOM-treated mice.</p> <p>Finally,
it is the case that several million individuals are taking thiazolidinediones
for management of type II diabetes. It would seem that an epidemiological
analysis of these individuals might, once and for all, determine if PPAR<italic>γ</italic> agonists have chemopreventive efficacy. Our
initial attempts to collect data on time to formation of a second polyp in
patients who are taking thiazolidinediones indicates that there are great many
confounding variables, which limit the power of such an analysis and may
account for the fact that few comprehensive anaylses of the effects of PPAR<italic>γ</italic> agonists on colon cancer
incidence have been reported [##REF##17192841##48##].</p> <p>In
summary, we conclude that both genetic and pharmacological data indicate that
PPAR<italic>γ</italic> suppresses some early stage in transformation
of colonic epithelial cells. We submit that the balance of evidence is
inconsistent with the hypothesis that PPAR<italic>γ</italic> promotes colon carcinogenesis under any
circumstances. Although it is unlikely that PPAR<italic>γ</italic> agonists will ever be developed as
chemopreventive agents, it is plausible that we may, by studying the mechanism
of action of PPAR<italic>γ</italic>, elucidate downstream effectors that may be
chemopreventive targets. Furthermore, it is possible that PPAR<italic>γ</italic> agonists may have clinical applicability in
prophylactic management of individuals who are at increased risk of colon
cancer due to large numbers of ACFs.</p> <title>4. PPAR<italic>γ</italic> AND INFLAMMATORY BOWEL DISEASE</title> <p>PPAR<italic>γ</italic> has become a potential pharmacological
target for treatment of inflammatory diseases of the colon, particularly
ulcerative colitis (UC). PPAR<italic>γ</italic> is highly expressed in both colonic
epithelial cells and macrophages critical for innate immunity and gut
homeostasis. Over the past decade, in
vitroand in vivo studies have defined an anti-inflammatory role for
macrophage and epithelial PPAR<italic>γ</italic> in regulating colonic inflammation.
Studies utilizing in vitro cell
culture models have established that thiazolidinedione PPAR<italic>γ</italic> agonists can reduce NF<italic>κ</italic>B activation and inflammatory gene
expression in colonic epithelial cells [##REF##16614990##49##, ##REF##10449430##50##], macrophages [##REF##9748221##51##–##REF##9422509##54##], dendritic cells [##REF##12734379##55##–##REF##17822917##58##], and T-cells [##REF##17325128##59##, ##REF##10640751##60##]. However, the magnitude by
which thiazolidinediones reduce inflammatory gene expression and act directly
through PPAR<italic>γ</italic> has been confusing. The
anti-inflammatory effects of thiazolidinediones vary among studies due to
differences in cell models, the concentration, duration, and type of
thiazolidinedione (rosiglitazone, pioglitazone) used, as well as the context of
inflammation studied (i.e., inducing
agent-LPS, TNF-<italic>α</italic>, etc. [##REF##11561171##61##]). More importantly, thiazolidinediones
can reduce inflammation in both a PPAR<italic>γ</italic> dependent and independent manner, with
the latter resulting from the use of high concentrations [##UREF##4##62##, ##REF##15356214##63##]. Despite confusion, it has
been generally accepted that thiazolidinediones can reduce inflammatory gene expression via PPAR<italic>γ</italic> in epithelial and immune cells when
used at appropriate concentrations.</p> <p>Perhaps the strongest evidence for an
anti-inflammatory role of PPAR<italic>γ</italic> comes from landmark studies indicating 
that heterozygous PPAR<italic>γ</italic> deficient mice were more susceptible to
DSS- and TNBS-induced colitis [##REF##11283155##64##, ##REF##12479648##65##]. DSS-induced colitis, in
particular, is an acute inflammation model primarily driven by epithelial
disruption and macrophage infiltration. This data indicates that PPAR<italic>γ</italic> expression in certain cell types of the
colon plays an anti-inflammatory role. Recent studies elaborated on these
findings by showing that mice deficient in PPAR<italic>γ</italic> expression in epithelial cells and
macrophages displayed increased proinflammatory gene expression and
susceptibility to DSS colitis [##REF##16547072##66##, ##REF##17095756##67##]. These findings suggest that
PPAR<italic>γ</italic> expression in at least two cell types,
epithelial and macrophage, can protect against at least one model of acute
colitis (DSS). Questions remain regarding the importance of macrophage and
epithelial PPAR<italic>γ</italic> in other models of acute and chronic
colitis. For example, what is the role of macrophage or epithelial PPAR<italic>γ</italic> in a chronic colitis model driven by
T-cells? Likewise, little is known about the role of dendritic and T-cell
specific expression of PPAR<italic>γ</italic> in colitis, as PPAR<italic>γ</italic> knockout animals currently do not exist
for these cell types. Experimental models of colitis can be initiated by
distinct mechanisms and driven by infiltration of different cell types, both
epithelial and immune [##REF##16566291##68##–##UREF##5##70##]. Given that no single model
accurately mimics human colitis, much remains to be understood regarding the
tissue specific importance of PPAR<italic>γ</italic> in controlling gut inflammation.
Furthermore, the importance of tissue specific PPAR<italic>γ</italic> expression may depend largely on the
model of colitis examined, emphasizing the need to utilize multiple models to
accurately represent manifestations of human colitis. Collectively, knockout
animals have confirmed a potential protective role of PPAR<italic>γ</italic> in colitis but additional research is
still required to understand fully how tissue specific PPAR<italic>γ</italic> expression influences different
manifestations of colonic inflammation.</p> <p>Based on the evidence that (a) thiazolidinediones
can suppress inflammatory gene expression in vitro and (b) PPAR<italic>γ</italic> expression protects against the development
of colitis in several animal models, it seems logical that PPAR<italic>γ</italic> might be a good target for treatment of
gut inflammation. In reality, the preventative and therapeutic efficacy of
targeting PPAR<italic>γ</italic> with thiazolidinediones for treatment
of colitis is debatable. It remains unclear what phase, if any, would be best
for targeting PPAR<italic>γ</italic> with thiazolidinediones for treatment
of colitis: during the initiation, low grade, moderate, high grade, or
remission phases of colitis. Our knowledge is largely based on animal studies
in which acute preventive doses of thiazolidinediones were administered before
the initiation of colitis. When given acutely (0–3 days) before
inducing stimuli (i.e., DSS or TNBS) [##REF##10449430##50##, ##REF##11283155##64##–##REF##17095756##67##, ##REF##15735430##71##–##REF##12730872##73##]
or in the early life stages of animals that develop spontaneous cancer (IL-10<sup>−/−</sup> mice) [##REF##15735429##74##], thiazolidinediones provide
beneficial effects in the amelioration of inflammation. These data indicate
that at least one mode of PPAR<italic>γ</italic> action is to suppress the initiation of
colitis, and suggest that thiazolidinediones may be a useful chemopreventative
agent for the treatment of colitis. However, given their potential
cardiovascular side effects, it is unlikely that thiazolidinediones would be
approved as a chronic preventive agent for the management of gut inflammation.
Moreover, the effectiveness of long term-preventative thiazolidinedione
treatment on suppressing gut inflammation remains to be fully established. A
recent report indicates that long-term treatment of mice with rosiglitazone
exacerbated DSS-induced colitis [##REF##17510806##75##], raising concerns about the
preventative use of thiazolidinediones in gut inflammation.</p> <p>The alternative scenario is that thiazolidinediones
alone or in combination with anti-inflammatory/immunosuppressive drugs may be
used to therapeutically target active inflammation. However, data from human
and animal studies regarding the usefulness of therapeutic doses of thiazolidinediones
in the treatment of colitis are inconsistent. When given after the initiation
of DSS colitis, several studies found that thiazolidinediones had little or no
value in improving colitis symptoms [##REF##10449430##50##, ##REF##12479648##65##, ##REF##12730872##73##]. Likewise, therapeutic doses
of thiazolidinediones given after established inflammation in the IL-10<sup>−/−</sup> model of colitis provided no value [##REF##15735429##74##]. Similar results were
observed in a small open end clinical trial in which patients with moderate
colitis receiving rosiglitazone experienced only modest improvement [##REF##11774944##76##], however interpretation of
these results are difficult as the trial lacked a proper control group. In
contrast, a few studies have reported that therapeutic doses of rosiglitazone
improved colitis symptoms in DSS and TNBS colitis [##REF##11283155##64##, ##REF##15876425##77##, ##REF##16328104##78##]. Recently, a multicenter,
randomized, double blind placebo-controlled trial for treatment of mild to
moderately active UC with rosiglitazone showed clinical response in 44% of
patients [##REF##18325386##79##]. However, endoscopic
remission rates were not significantly different. The discrepancies in thiazolidinedione
effectiveness may reside with the doses of thiazolidinediones administered,
with the magnitude of inflammation at the time of thiazolidinedione
administration, or differences in scoring. Alternatively, the anti-inflammatory
actions of thiazolidinediones may be inhibited or not strong enough to suppress
inflammation during active colitis. Most likely, however, the lack of
therapeutic efficacy of thiazolidinediones during active colitis can be
explained by a loss of PPAR<italic>γ</italic> expression and/or activity that
coincides with the level of inflammation. Indeed, PPAR<italic>γ</italic> levels have been shown to be
downregulated in epithelial cells [##REF##12730867##39##] and macrophages [##REF##12730872##73##] during colitis. Moreover, Katayama
et al. showed that the lack of therapeutic responsiveness to thiazolidinediones
during colitis could be restored by adenoviral-mediated reexpression of PPAR<italic>γ</italic> in the colon [##REF##12730872##73##]. In
addition, Necela et al. showed that NF<italic>κ</italic>B drives down PPAR<italic>γ</italic> expression in response to lipopolysaccharide,
thereby obviating the actions of PPAR<italic>γ</italic>
and promoting an inflammatory state in macrophages [##UREF##6##80##].</p> <p>In
summary, although the current data supports a role for PPAR<italic>γ</italic> expression and activation in epithelial
and immune cell types in the control of colonic inflammation, it remains
unclear whether targeting PPAR<italic>γ</italic> with thiazolidinediones will be an
effective strategy for treating gut inflammation. While animal models suggest a
favorable role of thiazolidinediones in chemoprevention, the efficacy and
safety of long-term use of thiazolidinediones as preventative agents or
maintenance therapy in UC patients remains to be assessed. Likewise, the use of
thiazolidinediones as therapeutic agents for treatment of colitis is
controversial. It remains unclear during what clinical phase of inflammation thiazolidinediones
would be most effective for treating UC patients or which patients would be
most likely to benefit from treatment. Moreover, there is considerable concern
regarding whether the adverse effects of thiazolidinediones would outweigh the
potential benefit for patients with UC. In general, the majority of studies are
in agreement that thiazolidinediones may be better exploited for therapeutic
treatment of mild-moderate active colitis rather than during severe
inflammation. Our understanding of the preventative and therapeutic potential
of targeting PPAR<italic>γ</italic> with thiazolidinediones is largely
limited by several factors, including the lack of (a) experimental usage of
distinct models of colitis, (b) understanding of tissue specific roles of PPAR<italic>γ</italic> in different models of colonic
inflammation, (c) understanding of factors affecting thiazolidinedione efficacy
(PPAR<italic>γ</italic> levels, etc.), (d) understanding of the mechanism of the anti-inflammatory
actions of PPAR<italic>γ</italic>, and (e) understanding of the adverse effects of short- and long-term
use of thiazolidinediones during inflammation. Additional animal and clinical
studies should resolve these discrepancies and provide further insight into the
appropriate use, preventative or therapeutic, of thiazolidinediones for
treatment of gut inflammation.</p>
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PPAR Res. 2008 Jul 6; 2008:148687