Interleukin (IL)-1

IL-1 is a potent pro-inflammatory cytokine that activates many immune and inflammatory cells. It is a type 1 pro-inflammatory cytokine that is up regulated in the intestinal mucosa of IBD patients (Ligumsky et al., 1990). It is released by monocytes, macrophages, neutrophils and endothelial cells. IL-1 consists of IL-1α and IL-1β, which bind to IL-1 receptor on target cells: IL-1α is expressed in many cell types while IL-1β expression is induced mostly in response to microbial molecules (Dinarello, 2009). IL-1 is up regulated in plasma and tissue in CD and UC (Mahida et al., 1989 ; Casini-Raggi et al., 1995 ; Turner et al., 2014).

26 1.3.1.2 Tumor Necrosis Factor (TNF-α)

Tumor Necrosis Factor (TNF) is an important mediator of inflammation and it is secreted early on in the inflammatory response from macrophages, monocytes, T cells, mast cells, fibroblasts and neurons (Tracey et al., 2008). TNF binds to its receptors, TNFR1 and TNFR2 and subsequently activates NF-αB and leads to the induction of pro-inflammatory gene expression. A hallmark of severe IBD is the overproduction of TNF-α in colonic mucosa (Li et al., 2010). In addition, TNF-α induced necroptotic cell death in the terminal ileum of patients with CD (Günther et al., 2011). Interestingly, Mucin genes and protein expression in intestinal cell lines and animal models are similarly influenced by TNF (Elson et al., 1995 ; Enss et al., 2000) .

1.3.1.3 Monocyte chemoattractant protein 1 (MCP1)

Chemokines play an important role particularly in the recruitment of monocytes, neutrophils, and lymphocytes, as well as inducing chemotaxis through the activation of G-protein-coupled receptors. MCP1 is one of the chemokines produced by different cells such as dendritic cells, macrophage, endothelial cells, and fibroblasts. It is responsible for monocytes and T-lymphocytes recruitment to sites of inflammation (Tesch et al., 1999).

Interestingly, MCP1 levels are elevated after inflammatory stimuli such as IL-1 and TNF-α (Luther and Cyster, 2001). IL-1β can induce the expression of MCP1 and the absence of IL-1β leads to down-regulation of MCP1 at the mRNA and protein levels (Rovin et al., 1999 ; Kirii et al., 2003). In UC cases, MCP1 is up-regulated and monocyte recruitment into the colonic mucosa is, leading to an intensified mucosal immune response (Reinecker et al., 1995; Grimm et al., 1996). The expression of MCP1 is significantly higher in the mucosa of UC patients as compared to mucosa of healthy patients, indicating that the production of MCP1 may contribute to the development of UC (MacDermott et al., 1998 ; Uguccioni et al., 1999 ; Banks et al., 2003).

27 Table 1 Selected key cytokines activities implicated in the pathogenesis of IBD

Cytokines Source in the mucosa Potential function in the IBD pathogenesis

IFNα, β DCs Promote epithelial regeneration and induce

IL-10 producing cells

TNF-β Th1 and Tc cells NO production, cell death

TNF-α Macrophages, mast cells induces death epithelial cells, inflammation, and pain

IL-1 Neutrophils Augments recruitment of neutrophils, Stimulates IL-6 Macrophages production by macrophages, inflammation.

IL-10 Inhibits IL-10 knockout mice develop enterocolitis

TNFα, IL-1, 2, 6, 8, IFNɣ IL- 10 reduced severity of colitis and nitric oxide production

Macrophages, T lymphocyte

TGFβ Promotes wound healing, Increase TGF-β levels in IBD epithelial restitution TGF-β knockout mice develop colitis

MCP-1 monocytes and T lymphocyte Recruiting leucocytes into the colonic lesions

1.4 Endoplasmic reticulum stress in the intestinal epithelial cell and inflammatory bowel disease

ER stress is a hallmark of several diseases. Numerous environmental and genetic factors can alter the functionality of the ER, leading to the accumulation of misfolded protein in this organelle, resulting in ER stress. As previously discussed, one of the cellular adaptations to unresolved ER-stress, is the activation of the unfolded protein response (UPR). Secretion of antimicrobial peptides and mucins is decreased after UPR

28 activation and this may reduce the capability of the mucosal barrier (McGuckin et al., 2010). The intestinal epithelium contains four types of secretory epithelial cells that are exposed to exogenous antigens and these include the absorptive epithelium, goblet, Paneth, and enteroendocrine cells (Barker et al., 2007). Interestingly, the secretory cells including Paneth cells and goblet cells are very susceptible to ER stress, and the UPR function is important to maintain epithelial cell homeostasis (Maloy and Powrie, 2011).

Importantly, intestinal secretory cells release important components of the mucosal barrier to prevent mucosal infection and inflammation. Chronic ER stress and defects in UPR signaling may contribute to inflammation and inflammation-related human diseases.

Recently, it has been reported that multiple components of the UPR signaling are linked to ER stress leading to inflammatory bowel disease (IBD) (McGuckin et al., 2010).

Activation of IRE1 pathway is also associated with intestinal inflammation. Several genes, including XBP1, AGR2 and ORMDL3, encode proteins associated with ER function and are implicated in susceptibility to Crohn’s and (CD) and Ulcerative colitis (UC) (Kaser et al., 2010). In fact, Agr2 knockout mice result in the accumulation of misfolded proteins in the ER (Zhao et al., 2010). The deletion of X-box-binding protein1 (XBP1), which is a key component of ER stress response, in the intestinal epithelium of mice led to the induction of ER stress, inflammation and spontaneous colitis (Kaser et al., 2008). Furthermore, XBP1 deficiency in intestinal tissues increases CHOP, BiP and ATF4 levels (Garg et al., 2012). In contrast, under ER stress-induced inflammation conditions, CHOP did not activate the apoptotic pathway even though it did induce activation of IL-1β (Endo et al., 2006).

The intestinal epithelium is the first to be exposed to trillions of commensal microbes and various metabolic products derived from the host and its microbiota.

Intestinal epithelial cells provide a barrier between the host and microbiota to maintain tissue homeostasis. However, disruption of the intestinal epithelium allows translocation of many commensal bacteria across the intestinal layer, thus inducing chronic mucosal inflammation. Furthermore, toxins or infectious components from invading pathogens can affect the protein folding machinery in the ER, ultimately causing ER stress (Kaser et al., 2013 ; Smith, 2014). Epithelial cells not only act as a physical barrier but can also function in the maintenance of mucosal homeostasis (Luo and Cao, 2015). Secretory cells

29 decrease the release of components in the mucosal barrier when faced with severe ER stress conditions and can lead to premature apoptosis (Kim et al., 2008). Paneth cells play an important role in mucosal innate immunity by secreting antimicrobial peptides and multiple defensins in the small intestine, and when Paneth cells are disrupted, the release of antimicrobial peptides is decreased and these has been linked to Crohn’s ileitis (Garrett et al., 2010). Additionally, changes in the expression of defensins and proliferation of Paneth cell are linked to IBD (Shi, 2007), Goblet cells produce mucins in both small and large intestines. MUC2 mucin is a highly glycosylated glycoprotein that undergoes N-glycosylation in the ER and O-N-glycosylation in the Golgi apparatus before being secreted into the intestinal lumen (Kim and Ho, 2010). Mutations in Muc2 lead to the accumulation of MUC2 in the ER of goblet cells of mice and resulted in decreased mucin secretion and an impaired mucus layer that may be ultimately linked to ulcerative colitis (Heazlewood et al., 2008). Taken together, the accumulation of immature glycoproteins induces ER stress in the cells and link to a reduction of mucin secretion. Furthermore, increased production of type1/ Th1 and type2/Th2 cytokines in mice expressing a mutant Muc2 gene led to the spontaneous development of distal colitis and an increased susceptibility to DSS-induced colitis (Heazlewood et al., 2008). Cytokines associated with infections and inflammations induce oxidative stress, and that has been shown to indirectly aggravate ER stress by, increasing misfolded proteins (Cornick et al., 2015).

30

1.5 Aim of the study

Considering the importance of proper ER performance on the overall cellular fitness and function of the intestinal epithelium, it is crucial to understand the factors that trigger ER stress and the ensuing effects on the epithelial barrier. Furthermore, with the instances of IBD on the rise, it has become necessary to unravel the link between cytokine-induced inflammation, ER malfunction and intestinal disease. This study focuses on analyzing the effects of pro-inflammatory mediators on ER fitness and the subsequent influence of ER stress on intestinal epithelial cell polarity, protein folding and expression of intestinal proteins.

The purpose of this study is 1) to determine the ability of a cytokine cocktail made of TNF-α, IL-1, MCP-1 to induce ER stress 2) to investigate the effect of cytokine induced-ER stress on intestinal epithelial cell polarity, barrier integrity, protein folding and the expression of specific proteins from the apical membrane such as sucrase-isomaltase and ezrin, and from the basolateral membrane such as ZO-1, and Cx43 and 3) to explore the role of hypoxia-induced ER stress and its effect on barrier integrity.

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