Modulation of tight junction structure and function by cytokines
Introduction
Intercellular tight junctions are highly regulated, complex structures that form a dynamic barrier between different physiologic compartments [1]. Alteration of tight junction function is an important pathogenetic process in many human diseases [2]. A variety of exogenous agents including bacterial toxins and dietary glucose can affect intercellular tight junction function thereby altering paracellular permeability [3], [4], [5]. Recently, endogenous agents including many cytokines and growth factors have also been shown to regulate tight junction function in both epithelia and endothelia. However, the mechanisms by which cytokines regulate tight junction function are poorly understood.
Recombinant human cytokines and in vitro cell culture models have greatly facilitated studies related to understanding the influence of cytokines on tight junction function [6]. The recent identification of several tight junction proteins has permitted direct examination of cytokine effects on the molecular structure of tight junctions [7], [8]. Expanding data on the effects of cytokine modulation of tight junctions has provided important new insights into the pathogenesis of disease and raised the possibility of novel therapeutic approaches. A complete review of all the cytokines shown to modulate epithelial and/or endothelial tight junction function is beyond the scope of this article. Therefore, in this paper, we have reviewed the influence of selected cytokines on tight junction function. Particular emphasis will be placed on cytokines whose effects on the molecular architecture of tight junctions and on the associated actin cytoskeleton have been most thoroughly studied. Data on other cytokines affecting tight junction barrier function will be summarized and presented in tabular form (Table 1).
Section snippets
Functional effects of IFNγ on epithelial cell barrier function
Interferon-γ (IFNγ) is a 20–25 kDa glycosylated protein produced by activated T-cells and natural killer cells. During an inflammatory response, IFNγ modulates epithelial and endothelial cell functions in addition to performing its role as an immunoregulatory molecule [9], [10], [11]. IFNγ was first shown to affect epithelial barrier function in an in vitro cell culture system utilizing model intestinal epithelial cell monolayers [12]. Polarized T84 intestinal epithelial cell monolayers
Functional effects of hepatocyte growth factor on epithelial cells
HGF is a 103 kDa (approximately) disulfide-linked, heterodimeric protein that is produced chiefly by mesenchymal cells and influences epithelial function in a paracrine fashion [30], [31], [32]. HGF is synthesized as an inactive single chain precursor and must be proteolytically cleaved to become functionally active. We have documented an HGF-induced decrease in TER of T84 intestinal epithelial monolayers. This drop in TER is a delayed phenomenon that peaks 48 h after incubation with
Functional effects of TNFα on epithelial intercellular junctions
TNFα is a 17 kDa proinflammatory cytokine produced mainly by mononuclear cells which influences endothelial, smooth muscle and epithelial cells in a paracrine fashion [40], [41], [42], [43]. Numerous studies have documented TNFα-induced effects on barrier function in both epithelial and endothelial cells. Initial studies, performed in polarized LLC-PK1 porcine renal epithelial cell monolayers, demonstrated a TNFα-induced decrease in transepithelial resistance followed by a increase in TER which
Epidermal growth factor (EGF)
EGF is a 6.4 kDa protein which initiates multiple cellular responses including auto-phosphorylation of its own receptor, generation of inositol phosphates, increasing intracellular calcium and initiation of cell mitosis [57], [58]. Despite the fact that EGF treatment of cell monolayers initiates mitosis, EGF stimulation has been shown to increase the TER of polarized LLC-PK1 epithelial cells [59]. This finding was accompanied by a mild (15%) increase in transepithelial mannitol flux but no
Transforming growth factor-β1 (TGFβ1)
TGFβ1 is a 25 kD disulfide-linked homodimer produced by platelets, lymphocytes, macrophages and endothelial cells. TGFβ1 is a potent growth inhibitor of immune cells, endothelial cells, and epithelial cells [62], [63]. TGFβ1 was shown to enhance the barrier function of T84 intestinal epithelial monolayers and to promote intestinal epithelial restitution [18], [64], [65], [66], [67]. Subepithelial myofibroblasts enhance T84 monolayer barrier function by secreting TGFβ1 [66]. TGFβ1 not only
Conclusion
Several cytokines and growth factors have been shown to influence tight junctions both in vitro and in vivo. These effects have been documented in epithelial and endothelial cells and therefore have important implications for both epithelial barrier function and vascular permeability. While the majority of cytokines analyzed so far increase epithelial and endothelial cell permeability, certain cytokines exert the opposite effect. Individual cytokines may also induce differential effects on
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