1 Division of Gastrointestinal Pathology, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322; and 2 Division of Gastrointestinal Pathology, Department of Pathology, Wayne State University, Detroit, Michigan 48201
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ABSTRACT |
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The epithelial lining of the
gastrointestinal tract forms a regulated, selectively permeable barrier
between luminal contents and the underlying tissue compartments.
Permeability across the epithelium is, in part, determined by the
rate-limiting barrier of the paracellular pathwaythe most apical
intercellular junction referred to as the tight junction (TJ). The TJ
is composed of a multiprotein complex that affiliates with the
underlying apical actomyosin ring. TJ structure and function, and
therefore epithelial permeability, are influenced by diverse
physiological and pathological stimuli; here we review examples of such
stimuli that are detected at the cell surface. For example, luminal
glucose induces an increase in paracellular permeability to small
molecules. Similarly, but by other means, cytokines and leukocytes in
the vicinity of the epithelium also regulate TJ structure and
paracellular permeability by influencing the TJ protein complex and/or
its association with the underlying actin cytoskeleton.
epithelial cells; leukocytes
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INTRODUCTION |
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THE EPITHELIAL LINING of the gastrointestinal tract forms a regulated, selectively permeable barrier permitting the passive entry of luminal nutrients, ions, and water while restricting pathogen access to underlying tissue compartments. Permeability properties of the epithelium are dynamically regulated by diverse physiological and pathological stimuli (25). Additionally, enhanced paracellular permeability across intestinal epithelium occurs in patients with Crohn's disease as well as their first-degree relatives, suggesting that altered tight junction (TJ) permeability may be a contributing factor in this process (18). Similarly, altered TJ ultrastructure and increased paracellular permeability have been documented in colonic epithelium from patients with ulcerative colitis, suggesting that the TJ may also be involved in the pathogenesis of ulcerative colitis (28). In the latter case, it is presumed that the TJ defects are secondary to the array of inflammatory signals that characterize this state.
Paracellular permeability is regulated primarily by the most apical epithelial intercellular junction, the TJ or zonula occludens (because this is the rate-limiting barrier in this transport pathway). The TJ forms a regulated, semipermeable barrier and acts as a fence that segregates protein (and partially lipid) components of the apical and basolateral plasma membrane domains. This distinctive barrier and fence function of TJs is vital in regulation of paracellular movement of fluids and solutes, thereby establishing distinctive microenvironments on both sides of polarized cells.
The structure of the TJ was the topic of a recent Themes article and can be briefly summarized. By electron microscopy (EM), the TJ appears as a series of discrete contacts or "kisses" between the plasma membranes of adjacent cells. In addition, the TJ appears as a series of anastomosing and branching fibrils within the plane of the membrane that correspond to sites of membrane contact by freeze-fracture EM. Such fibrils appear to have the capacity of dynamic rearrangement within the membrane bilayer and have been shown to harbor proteins. The TJ is composed of a multiprotein complex. It is the combination of the protein complex and membrane lipids that makes this region of the cell membrane unique (22). Moreover, the TJ is linked to the apical perijunctional actomyosin ring. This association regulates the overall permeability and charge-selective properties of the TJ. TJ proteins identified so far include transmembrane proteins occludin and claudin and cytoplasmic plaque proteins ZO-1, ZO-2, ZO-3, cingulin, and 7H6 (19).
The paradigm of protein organization in TJ is analogous to other intercellular junctions, being composed of transmembrane proteins that mediate adhesive functions and are linked to underlying plaque proteins that in turn associate with the cytoskeleton. Although the adherens junction (AJ) is spatially distinct and subluminal to the TJ, these junctions form a functional unit referred to as the apical junction complex. Both are structurally related to the perijunctional actomyosin ring. In vascular endothelial cells, the AJ may also play a role in regulation of paracellular permeability and is also involved in diapedesis of circulating leukocytes (10).
The events pertaining to regulation of tight junctions by extracellular
stimuli are summarized in Fig. 1 and
discussed below.
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PHYSIOLOGICAL REGULATION OF TIGHT JUNCTIONS BY NA+-NUTRIENT COTRANSPORT |
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Although TJ permeability had been known previously to be regulated by intracellular second messengers, one of the first examples of physiological TJ regulation by an extracellular event was described in 1987 (25). In these studies it was shown that addition of luminal glucose to segments of rodent small intestine mounted in Ussing chambers caused a significant increase in paracellular permeability to small molecules. This was accompanied by simultaneous increases in conductance and decreases in transmucosal resistance. Despite the uncertainties expressed in the literature regarding the in vivo relevance of Na+-nutrient cotransport-dependent TJ regulation (34), Na+-glucose cotransport-dependent regulation of small intestinal permeability has been demonstrated in vivo in rats and has recently been extended to healthy human subjects as well (32).
EM examination of TJ structure during Na+-glucose cotransport demonstrated the formation of intrajunctional TJ dilatations that were penetrated by an oligopeptide tracer applied to the apical (luminal) surface (1). Immunoelectron microscopic evaluation of the TJ protein ZO-1 during glucose-induced regulation of paracellular permeability showed a spatial dissociation between ZO-1 and the morphologically identified TJ, suggesting that the biochemical association between ZO-1 and the junctional fibrils is modified during physiological regulation of TJ permeability.
Early events in Na+-glucose cotransport-dependent TJ regulation. Further progress in understanding the mechanisms by which TJ permeability is regulated by Na+-glucose cotransport were possible only after the establishment of an in vitro model of physiological Na+-glucose cotransport-dependent TJ regulation (35). In this model, monolayers of Caco-2 cells expressing the Na+-glucose cotransporter SGLT-1 exhibit 30% decreases in transepithelial resistance (TER) after activation of Na+-glucose cotransport (35). The model has been used to characterize early and late events in the signaling pathway linking Na+-glucose cotransport to TJ regulation. For example, it was reported recently that initiation of Na+-glucose cotransport causes a mild cytoplasmic alkalinization that is dependent on the activation of the brush border Na+/H+ exchanger isoform NHE3 (30). Moreover, inhibition of NHE3 causes increases in TER (31). Thus one current working hypothesis is that NHE3 activation may be a critical component of the signaling pathway for Na+-glucose cotransport-dependent TJ regulation. Because NHE3 is a major route of Na+ absorption in the small intestine, Na+-glucose cotransport may also trigger a shift from a quiescent to an actively transporting epithelium.
Late events in Na+-glucose
cotransport-dependent TJ regulation.
In addition to intrajunctional dilatations, EM of intestinal mucosae
with active Na+-glucose cotransport identified condensation
of the perijunctional cytoskeleton (14). The cultured cell
model of Na+-glucose cotransport-dependent TJ regulation
has been used to evaluate a biochemical marker of actomyosin
contractionphosphorylation of the myosin II regulatory light chain.
Initiation of Na+-glucose cotransport induces an increase
in phosphorylation of myosin light chain (35). To
determine whether these increases in myosin light chain phosphorylation
were mechanistically linked to TJ regulation, the effects of myosin
light chain kinase inhibitors were also evaluated (35). In
both cultured monolayers and isolated mucosae, these inhibitors
prevented Na+-glucose cotransport-dependent increases in TJ
permeability (35). Moreover, inhibition of NHE3 exchange
also reduced myosin light chain phosphorylation (31),
consistent with the hypothesis that Na+-glucose
cotransport-dependent activation of NHE3 is linked to increased myosin
light chain phosphorylation. Thus one could speculate that initiation
of Na+-glucose cotransport leads to activation of NHE3,
increased phosphorylation of myosin light chain, contraction of the
perijunctional actomyosin ring, and, ultimately, increased permeability
of intestinal TJs.
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INFLUENCE OF CYTOKINES ON TIGHT JUNCTIONS |
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A broad array of cytokines, which serve as extracellular signals in a variety of physiological and pathological conditions, influence intercellular associations and permeability across epithelial and endothelial cells. Because a complete review of these cytokines is beyond the scope of this article, we focus on those more extensively studied in this regard.
Interferon-.
Interferon-
(IFN-
) is a 20- to 25-kDa glycoprotein released by
activated T cells and natural killer cells in inflammatory states. In
vitro models have been used to examine the influence of IFN-
on
intercellular junctions of epithelial and endothelial cells. The
initial studies addressing the influence of this cytokine on TJ used
the intestinal epithelial cell line T84 (15, 39). These
studies demonstrated that IFN-
induced an increase in paracellular permeability as determined by measurement of TER to passive ion flow
and increased paracellular flux of solutes such as mannitol. These
functional readouts are supported by morphological and biochemical modification of the TJ protein complex. Decreased expression of the TJ
cytoplasmic plaque protein ZO-1 is associated with redistribution of
occludin and ZO-2 from the lateral membrane of the TJ under this
condition. The IFN-
-induced disassembly of the TJ protein complex
coincides with disruption and disorganization of the apical F-actin
pool. Such morphological effects are also accompanied by a change in
the differential detergent solubility of ZO-1 and ZO-2. No change in
phosphorylation of these proteins was observed. These studies emphasize
the link between the actin cytoskeleton and TJ and its critical role in
dynamic regulation of paracellular permeability. Nonetheless, the
detailed mechanisms by which this cytokine influences epithelial
paracellular permeability and the signaling cascade linking IFN-
and
TJ have not yet been defined. One confounding feature of the study of
this event is that the response observed occurs days after the original
stimulus and requires new protein synthesis; thus the response is not
acute phase but paired with a more global remodeling of epithelial architecture.
Hepatocyte growth factor.
Hepatocyte growth factor (HGF) is chiefly synthesized by
mesenchyme-derived cells and influences epithelial permeability in a
paracrine fashion via ligation with its receptor, c-met. It was previously documented that HGF induces a decrease in TER of T84
epithelial monolayers (21) that is maximal at 48 h.
The HGF-induced fall in TER is analogous to that induced by IFN-. Both cytokines decrease TER from ~1,000 to ~300
· cm2, consistent with a moderate increase in
paracellular permeability. Structural studies to analyze the influence
of HGF on intercellular junctions have not yielded unifying results to
suggest mechanisms by which this factor influences epithelial
permeability. Depending on the origin of epithelial cells, variable
effects of HGF on protein organization in the TJ versus its subjacent
AJ have been proposed. Initial epithelial cell-cell adhesion is
regulated by cadherins in the AJ. Such initial contacts are stabilized
by association of the AJ protein complex with the underlying actin
cytoskeleton. A renal epithelial cell line, Madin-Darby canine kidney
(MDCK) cells, has been extensively used to explore mechanisms by which HGF influences epithelial barrier function. In subconfluent cultures of
MDCK cells, HGF inhibited the morphological assembly of AJ and
overlying TJ (26). In this study, the authors examined the influence of HGF on junction assembly by investigating the
localization, stability, phosphorylation, and detergent solubility of
the major AJ proteins. HGF-induced inhibition of junction assembly was
associated with an increase in the Triton X-100 insoluble pool of
E-cadherin and plakoglobin without influencing the concentration of
these proteins. These changes were accompanied by altered
phosphorylation patterns of E-cadherin as determined by partial
proteolytic peptide mapping. In regard to HGF and TJ, the results are
variable and somewhat controversial depending on epithelial cell type,
and they range from an HGF effect on distribution of ZO-1 in TJ to no
change at all (7, 21). The signal transduction cascade(s) that mediates HGF-induced disassembly of intercellular junctions and
cell movement has also not been completely described. Ras-induced activation of both mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3-kinase) has been suggested.
TNF-.
TNF-
is a 17-kDa proinflammatory cytokine produced mainly by
mononuclear cells, and it influences barrier function of epithelial and
endothelial cells. A biphasic response of TNF-
on TER has been
reported in a porcine renal epithelial cell line, LLC-PK1 (16). In this study, an initial fall in TER and
increased paracellular permeability was followed by an increase in TER.
The latter phase correlated with decreased relative anion selectivity
of TJ (16). This study using pharmacological inhibitors
suggested a role for tyrosine kinase and protein kinase A in mediation
of the effects of TNF-
on this cell type. However, Schmitz et al.
(29) showed that, in the intestinal epithelial cell lines
HT29 and Caco-2, TNF-
induces a fall in TER without the subsequent
rebound. The only morphological correlate in this study was a decrease
in the TJ strand complexity by freeze-fracture EM (29). In
HUVEC, TNF-
has been documented to induce increased intercellular
gaps, an event associated with dispersion of VE-cadherin from AJ and
mediated at least in part by the Rho family of GTPases
(37). In combination with IFN-
, TNF-
induces a focal
loss of cadherin-5 in intercellular associations of endothelial
cells and has been implicated in facilitation of passage of blood
macromolecules and cells to the interstitium (38).
Other cytokines.
Many other cytokines have been investigated in regards to
epithelial/endothelial barrier function. Transforming growth factor (TGF)-1 has been reported to promote barrier function in human enterocytes (36). Exposure of the epidermal A431
cell line to epidermal growth factor (EGF) promotes TJ assembly. EGF
enhances apical redistribution of actin and phosphorylation of TJ
cytoplasmic plaque proteins ZO-1 and ZO-2 and intercellular junction
assembly of subconfluent monolayers. Other cytokines such as
interleukin (IL)-1, IL-4, IL-13, TGF-
, insulin-like growth factor
(IGF)-I and -II, and vascular endothelial growth factor (VEGF) have
been documented to decrease the barrier properties of
epithelial/endothelial cells. As discussed above, mechanisms ranging
from redistribution of TJ proteins and altered actin cytoskeleton have
been suggested to mediate the cytokine effects on barrier properties of
epithelial or endothelial cells.
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MODULATION OF INTERCELLULAR ASSOCIATIONS OF EPITHELIAL AND ENDOTHELIAL CELLS BY LEUKOCYTES |
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Transmigration of immune cells across vascular endothelium and epithelium is observed during both normal immune surveillance and in pathological conditions associated with an inflammatory response. During a normal immune response, passage of migrating cells is rapid and is not associated with morphological damage to intercellular junctions of endothelial and epithelial cells. Unlike the well-characterized events involved in adhesion of leukocytes to activated endothelium, the mechanisms controlling transmigration of these cells are less well characterized. Moreover, inflammatory states are associated with an influx of leukocytes and release of cytokines that themselves influence TJs and paracellular permeability across endothelial and epithelial cells.
Migration of immune cells from the vasculature into tissues during a normal immune response is rapid. Human polymorphonuclear leukocytes (PMN) can be stimulated to migrate across HUVEC monolayers toward N-formylmethionyl-leucyl-phenylalanine (fMLP). At a low PMN-to-endothelial cell ratio (1:1), no change in barrier function of monolayers was observed, suggesting that intercellular junctions opened to allow passage of migrating cells and then rapidly resealed as determined by measurement of TER and albumin permeability (11). A comparable conclusion was drawn from an earlier study of similarly directed leukocyte migration across epithelia at low density (20). Morphological analysis by EM demonstrated that the plasma membranes of cells in the process of traversing the endothelial monolayers maintained a close association with the lateral membrane of the monolayer. Such physical affiliations might result in maintenance of solute barrier function. However, when the number of PMN stimulated to migrate across endothelial monolayers increased, the paracellular permeability was markedly increased. In addition, Huang et al. (12) investigated mechanisms by which transmigrating PMN induced transient opening of intercellular junctions. Rise in intracellular Ca2+ after binding of activated PMN to endothelial cells has been observed in parallel with increase in monolayer permeability, suggesting that Ca2+, acting as a second messenger, can signal to transiently open intercellular junctions (6, 12). The intercellular junction proteins such as VE-cadherin have been implicated in regulation of leukocyte transmigration. Regulation of PMN transendothelial migration by VE-cadherin has been determined with the use of blocking anti-VE-cadherin antibodies that disrupt VE-cadherin cell-cell interactions. In this scenario, enhanced monolayer permeability and PMN transendothelial migration were observed (10). Moreover, intravenous administration of anti-VE-cadherin antibody in mice enhanced migration of PMN to an inflamed peritoneum. It is unclear whether such results were obtained because of antibody-mediated disruption of AJ or because of inhibition of junction resealing after the passage of PMN. Recently, another intercellular junction protein, JAM, that localized to the apical junction complex was reported to influence monocyte transmigration in a mouse model of skin inflammation (17). However, in an in vitro model of PMN transmigration across epithelial monolayers, antibodies to JAM did not influence transmigration of leukocytes (13). Analogous to endothelial cells, migration of low-density PMN across epithelial monolayers in the physiologically relevant (basolateral toward apical) direction is associated with a transient fall in TER that rapidly returns to normal. With increasing PMN-to-epithelial cell ratios, increased damage is observed, resulting in damaged intercellular associations and loss of epithelial cells that manifests as microscopic wounds in the monolayer. However, the initial increase in paracellular permeability is not simply the result of PMN physically impaling intercellular associations of epithelial cells. Addition of PMN to basolateral surfaces of epithelial cells (physiologically relevant) is associated with a fall in TER that is independent of PMN transmigration. The mechanism of this effect is as yet not completely understood and is likely to involve signaling events between PMN and epithelial cells.
Intraepithelial lymphocytes (IELs) constitute one of the largest
lymphocyte populations in the body and comprise a distinct T lymphocyte
fraction that resides in close proximity with epithelial cells.
Increased IELs and a decrease in epithelial barrier function are
observed in a number of chronic inflammatory conditions of the
gastrointestinal tract. Such disorders include lymphocytic colitis,
spruelike disorders, and chronic idiopathic conditions such as
inflammatory bowel disease. In an in vitro model of IEL homing, IELs
migrate into intestinal epithelial monolayers from the basolateral side
of the epithelium and reside in a subjunctional position. After 4 h of residence, approximately one-half of the IELs were found to exit
the monolayer from the basolateral side. In another study, E-cadherin
in AJ was found to be a counterreceptor for integrin-E
7 expressed
in IELs and to be important in mediating IEL migration into the
epithelial paracellular space (9). Addition of
mucosal-derived lymphocytes to T84 monolayers is associated with a
decrease in barrier function that requires direct lymphocyte contact
with the basolateral membrane of epithelial cells. IFN-
, IL-4, and
IL-10 appear to be the major barrier-disruptive cytokines released by
intraepithelial T lymphocytes. These cytokines influence transepithelial migration of PMN. Incubation of T84 monolayers with
IFN-
has been shown to downregulate transepithelial migration of PMN
in the basolateral to apical direction (3). The
IEL-released IFN-
, when added to T84 monolayers, was not of a
sufficient concentration to explain loss of epithelial barrier
function. However, the concentration of cytokines in the
microenvironment of lymphocytes and epithelial cells may be
significantly higher than cell supernatant values. IL-4, also released
by IELs, decreases T84 monolayer TER when applied to the basolateral
surface (4). In addition, IL-4 incubation of monolayers
results in a decrease in PMN transmigration in addition to enhancing
adhesion to the apical surface by a
2-integrin-dependent, intercellular adhesion molecule-1 (ICAM-1)-independent mechanism. Incubation of T84 monolayers with TGF-
1 reduces the
barrier-disruptive effects of IFN-
, IL-4, and IL-10
(27). Thus cytokines released by IELs might play a
significant role in regulating epithelial barrier function and in
modifying transepithelial migration of inflammatory cells. However, the
mechanisms by which IELs modify properties and influence intercellular
junctions still remain to be defined.
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CYTOSKELETAL REGULATION OF TIGHT JUNCTIONS![]() |
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A role for myosin light chain phosphorylation in TJ regulation has also been suggested in a variety of epithelial models, including Na+-nutrient cotransport-dependent TJ regulation (as discussed above). Physiological Na+-glucose cotransport-dependent TJ regulation is rapid, reversible, size selective, and dependent on myosin light chain phosphorylation (35). This association of myosin light chain phosphorylation with TJ regulation has been noted in experimental systems as diverse as hepatocytes exposed to vasopressin and thrombin-stimulated endothelial cells. In addition to soluble mediators, actomyosin contraction occurring as a consequence of the interaction between adherent neutrophils and endothelial cells also appears to be capable of regulating paracellular permeability (5). Thus diverse stimuli such as nutrients, hormones, soluble and cellular inflammatory mediators, and bacterial adherence may all regulate TJ permeability via actomyosin tension/contraction.
Further evidence supporting the role of myosin light chain phosphorylation in TJ regulation comes from studies using epithelial cells transfected with a truncated myosin light chain kinase gene construct that lacks the inhibitory domain necessary for calmodulin dependence (8). The truncated myosin light chain kinase expressed in the transfected cells is continuously active. Hecht et al. (8) found that, when this construct was constitutively expressed in MDCK cells, monolayers developed TER that was <10% of that developed in control monolayers. Expression of a truncated myosin light chain kinase caused approximately threefold increases in myosin light chain phosphorylation and concomitant 20-30% decreases in TER that were reversible on treatment with myosin light chain kinase inhibitors (33).
Further details of the specific molecular interactions that link tension/contraction of the perijunctional actomyosin ring to TJ regulation are not known, but it is tempting to speculate that a multimolecular complex is involved. Likely members of this complex include ZO-1, which is both an actin-binding and cross-linking protein, as well as cingulin, which can interact with both ZO-1 and myosin II heavy chain. Thus it is reasonable to speculate that ZO-1 interactions with cingulin and actin, cingulin interactions with myosin, and actomyosin interactions serve as bridges that allow regulation of TJ by the perijunctional actomyosin ring. Consistent with this hypothesis, we recently observed that TJ proteins are present in specialized membrane microdomains with physical characteristics of detergent-insoluble glycolipid-rich membrane rafts (23) and that regulation of TJ permeability by myosin light chain phosphorylation causes a subtle change in the physical characteristics of these TJ membrane microdomains (33). Thus myosin light chain phosphorylation may cause changes in TJ protein-protein interactions as well as a reorganization of TJ membrane microdomains.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants DK-35932, DK-47662, DK-02503, DK-55679, and DK-56121.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Nusrat, Dept. of Pathology and Laboratory Medicine, Emory Univ., WMRB, 2335, Atlanta, GA 30322 (E-mail: anusrat{at}emory.edu)..
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