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Is Osteopontin a Friend Or Foe of Cell Apoptosis in Inflammatory

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Is Osteopontin a Friend Or Foe of Cell Apoptosis in Inflammatory International Journal of Molecular Sciences Review Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Tomoya Iida ID , Kohei Wagatsuma, Daisuke Hirayama and Hiroshi Nakase * Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo 060-8543, Japan; [email protected] (T.I.); [email protected] (K.W.); [email protected] (D.H.) * Correspondence: [email protected]; Tel.: +81-11-611-2111; Fax: +81-11-611-2282 Received: 22 November 2017; Accepted: 19 December 2017; Published: 21 December 2017 Abstract: Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed. Keywords: osteopontin; apoptosis; gastrointestinal; liver; inflammation; cacinogenesis 1. Introduction Cancer epidemiologists have described three carcinogenesis factors: daily diet, smoking, and inflammation [1]. Although they have estimated that approximately 75% of cancers were due to those factors in 1980s, the percentage decreased to 43% in 2000s [1]. Among these three factors, inflammation is important because it does not involve lifestyle, unlike the other two factors. Inflammation is a physiological response of the body in the attempt to remove harmful stimuli, including damaged cells, irritants, pathogens, and sterile injuries such as cancer, and to begin the healing process. Myeloid cells, including macrophages and neutrophils, are the first immune cells involved in inflammation and are abundant in the tumor microenvironment [2,3]. Fibroblasts are also closely related to inflammation, and they produce collagen and other extracellular matrix components in the tumor microenvironment, stimulating cancer cell proliferation and angiogenesis. Various cytokines, chemokines, other molecules, including osteopontin (OPN), released from immune cells, and fibroblasts relate to the process of inflammatory carcinogenesis [4–7]. OPN is an extracellular matrix protein. It was identified in 1985 by Heingard et al., as a sialoprotein derived from bovine bone matrix [8]. OPN was also referred to as secreted phosphoprotein 1 (SPP1) and early T lymphocyte activation-1 (ETA-1). This plurality of names reflects the involvement of OPN in multiple physiological and pathological processes [9,10]. OPN belongs to the small integrin binding ligand N-linked glycoprotein (SIBLING) family [11]. Although this protein is produced as an approximately 32-kDa, the molecular mass actually ranges from 45 to 75 kDa because of extensive posttranslational modifications [12]. OPN is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer [13,14]. Int. J. Mol. Sci. 2018, 19, 7; doi:10.3390/ijms19010007 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 7 2 of 14 Int. J. Mol. Sci. 2018, 19, 7 2 of 15 and cancer [13,14]. OPN is expressed as a secreted OPN (sOPN) or an intracellular OPN (iOPN) isoformOPN is generated expressed from as a secreteddifferent OPNOPN (sOPN)translational or an initiation intracellular sites OPN [15].(iOPN) sOPN is isoform an extracellular generated proteinfrom different and relates OPN to translational various physiologic initiation sitesand pa [15thological]. sOPN is events, an extracellular including protein immune and regulation relates to [16],various inflammation physiologic [17], and pathologicaltumor progression, events,including and metastasis immune [18]. regulation On the [16 ],contrary, inflammation iOPN [ 17is], predominantlytumor progression, present and in the metastasis cytoplasm [18 ].and On lacks the th contrary,e N-terminal iOPN signal is predominantly sequence of sOPN present [15]. in The the expressioncytoplasm andof OPN lacks is the observed N-terminal in signalvarious sequence tissues of and sOPN cells, [15 ].including The expression intestinal of OPN epithelial is observed and immunein various cells tissues such andas macrop cells, includinghages, dendritic intestinal cells epithelial (DCs), and and T lymphocytes immune cells [19]. such as macrophages, dendriticOPN cellsplays (DCs), an important and T lymphocytes role in efficient [19]. development of T helper 1 (Th1) immune responses [20] andOPN cell plays survival an important by inhibiting role in apoptosis efficient development[21]. The association of T helper of OPN 1 (Th1) with immune apoptosis responses has been [20] elucidated.and cell survival In this review, by inhibiting we described apoptosis the [ 21role]. Theof OPN association in inflammatory of OPN withgastrointestinal apoptosis (GI) has beenand liverelucidated. diseases, In focusing this review, on weits association described the with role apoptosis. of OPN in inflammatory gastrointestinal (GI) and liver diseases, focusing on its association with apoptosis. 2. The Role of OPN in Immune Cells, Focusing on Its Association with Inflammation and Apoptosis 2. TheOPN Role has of specific OPN in roles Immune in each Cells, immune Focusing cell. on OPN Its Association plays an important with Inflammation role in acute and and Apoptosis chronic inflammation.OPN has Figure specific 1 rolesshows in how each OPN immune is involved cell. OPN in playsinflammation an important and apoptosis role in acute related and to chronic each immuneinflammation. cell. Figure1 shows how OPN is involved in inflammation and apoptosis related to each immune cell. FigureFigure 1. 1. TheThe role role of of osteopontin osteopontin in in immune immune cells cells focu focusingsing on on the the relationship relationship between between inflammation inflammation andand apoptosis. apoptosis. 2.1.2.1. Macrophage Macrophage Primarily,Primarily, OPN OPN not not only only stimulates stimulates migration, migration, accumulation, accumulation, and and retention retention of macrophages of macrophages at sitesat sites of injury of injury but but can can also also modulate modulate their their cyto cytokinekine production production by by promoting promoting Th1 Th1 cell-mediated cell-mediated immunityimmunity andand stimulating stimulating their their differentiation differentiation from monocytesfrom monocytes in both acutein both and chronicacute and inflammation. chronic inflammation.OPN controls severalOPN immunecontrols cellseveral functions, immune including cell monocytefunctions, adhesion, including migration, monocyte differentiation, adhesion, migration,and phagocytosis. differentiation, OPN has and multiple phagocytosis. functional OPN adhesive has multiple motifs, which functional allow interactionsadhesive motifs, with variouswhich allowcells, includinginteractions smooth with muscle,various endothelial,cells, including and smooth inflammatory muscle, cells. endothelial, One of the and representative inflammatory adhesive cells. Onemotifs of isthe the representative Arg-Gly-Asp adhesi (RGD)ve integrin motifs bindingis the Arg-Gly-Asp domain. The (RGD) integrin integrin binding binding domain domain. of OPN Themediates integrin interactions binding domain via αv ofβ1 ,OPNαvβ 3mediates, αvβ5, α interactionsvβ6, α5β1, andvia ααvβ8β1,1 αintegrinsvβ3, αvβ5, α [22vβ,623, α].5β In1, and addition, α8β1 integrinsthe adjacent [22,23]. Ser-Val-Val-Tyr-Gly-Leu-Arg In addition, the adjacent (SVVYGLR) Ser-Val-Val-Tyr-Gly-Leu-Arg sequence interacts with (SVVYGLR)α9β1, α4β1 ,sequence and α4β7 interactsintegrins, with which α9β1, are α4β present1, and α4 onβ7 integrins, the surface which of immuneare present cells on suchthe surface as macrophages, of immune cells T-cells, such and as macrophages,neutrophils [ 24T-cells,]. The and interaction neutrophils of OPN, [24]. The not interaction only with ofα4 OPN,and α not9 integrins only with but α4 and also α with9 integrins CD44, butinfluences also with migration CD44, ofinfluences macrophages. migration Of note, of OPN macrophages. inhibits macrophage Of note, apoptosisOPN inhibits by interacting macrophage with apoptosisα4 integrin by and interacting CD44 [25 with,26]. α Moreover,4 integrin and iOPN CD44 increases [25,26]. nuclear Moreov factorer, iOPN kappa-light-chain-enhancer increases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation through phosphorylation and Int. J. Mol. Sci. 2018, 19, 7 3 of 15 of activated B cells (NF-κB) activation through phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, α (IκBα) by inducing the IκB kinase α/β (IKKα/β) activity [27,28]. 2.2. Dendritic Cell (DC) OPN plays a key role in DC maturation, migration, and polarization [29]. The expression of OPN in immature DCs is higher than in mature DCs.
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