Involvement of the IL-22/REG Iα axis in ulcerative colitis

Sekikawa, Akira; Fukui, Hirokazu; Suzuki, Kazuyuki; Karibe, Toyohiko; Fujii, Shigehiko; Ichikawa, Kazuhito; Tomita, Shigeki; Imura, Johji; Shiratori, Keiko; Chiba, Tsutomu; Fujimori, Takahiro

doi:10.1038/labinvest.2009.147

Cited by 75 publications

(84 citation statements)

References 42 publications

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“…IL-6 and IL-8 are reported to induce REG Iα mRNA in vitro [18,21,22] and in vivo [39], and IL-11 [23], IL-22 [24], IFN-γ [25], IFN-β [12] and CINC-2β [26] are also reported to induce REG Iα mRNA. IL-6R and gp130 are known as signal transducers of IL-6.…”

Section: Cytokine/chemokine(s) Gene Expression In Msgmentioning

confidence: 96%

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome

Yoshimoto

Fujimoto

Itaya‐Hironaka

et al. 2013

Clinical and Experimental Immunology

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SummaryThe regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcriptionpolymerase chain reaction (RT-PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly higher than that of control. REG Iα protein was expressed highly in SS ductal epithelial cells. Anti-REG Iα autoantibodies in the sera were found in 11% of SS. All the MSG in the anti-REG Iα autoantibody-positive group showed REG Iα expression, whereas only 40% showed REG Iα expression in the anti-REG Iα autoantibodynegative group. The anti-REG Iα autoantibody-positive group showed significantly lower saliva secretion and a higher ratio of grade 4 (by RubinHolt) in sialography. These data suggest strongly that autoimmunity to REG Iα might play a role in the degeneration of MSG ductal epithelial cells in primary SS.

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Section: Cytokine/chemokine(s) Gene Expression In Msgmentioning

confidence: 96%

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome

Yoshimoto

Fujimoto

Itaya‐Hironaka

et al. 2013

Clinical and Experimental Immunology

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“…Of note, IL-22 is a unique cytokine that is produced by Th17 cells or NK cells, but targeted exclusively to IECs in the intestinal mucosa [70]. It has been shown that the IL-22-STAT3 pathway promotes epithelial regeneration through cell proliferation and increased secretion of factors such as RegIIIb, RegIIIc, or S100A9 [71][72][73]. Mizoguchi et al has shown that local production of IL-22 may promote tissue repair in a mice colitis model [74].…”

Section: Mechanism Of Epithelial Repair In Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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“…Total RNA was isolated from GI tissues with Trizol reagent (Invitrogen, Carlsbad, CA). Total RNA (4 g) was reverse-transcribed using oligo-dT primer (Applied Biosystems, Branchburg, NJ), and real-time RT-PCR was performed using 7900H Fast Real-Time PCR System (Applied Biosystems), as previously described (19). The set of primers for mouse Reg I, Reg II, Reg III␣, Reg III␤, Reg III␥, Reg III␦, Reg IV, and GAPDH were prepared as shown in Table 2.…”

Section: Animal Model Reg I Ko (Reg Imentioning

confidence: 99%

Expression ofRegfamily genes in the gastrointestinal tract of mice treated with indomethacin

Sun

Fukui

Hara

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Regenerating gene (Reg) family proteins, which are classified into four types, commonly act as trophic and/or antiapoptotic factors in gastrointestinal (GI) diseases. However, it remains unclear how these proteins coordinate their similar roles under such pathophysiological conditions. Here, we investigated the interrelationships of Reg family gene expression with mucosal cell proliferation and apoptosis in nonsteroidal anti-inflammatory drug (NSAID)-induced GI injury. GI injury was induced by subcutaneous injection of indomethacin into Reg I knockout (KO) and wild-type (WT) mice, and its severity was scored histopathologically. Temporal changes in the expression of Reg family genes, mucosal proliferation, and apoptosis were evaluated throughout the GI tract by real-time RT-PCR, Ki-67 immunoreactivity, and TUNEL assay, respectively. Reg I, Reg III family, and Reg IV were predominantly expressed in the upper, middle, and lower GI mucosa, respectively. Expression of Reg I and Reg III family genes was upregulated in specific portions of the GI tract after indomethacin treatment. Ki-67-positive epithelial cells were significantly decreased in the gastric and small-intestinal mucosa of Reg I KO mice under normal conditions. After treatment with indomethacin, the number of TUNEL-positive cells was significantly greater throughout the GI mucosa in Reg I KO mice than in WT mice. Expression of Reg I was independent of that of other Reg family genes in, not only normal GI tissues, but also indomethacin-induced GI lesions. Members of the Reg gene family show distinct profiles of expression in the GI tract, and Reg I independently plays a role in protecting the GI mucosa against NSAID-induced injury.Reg; nonsteroidal anti-inflammatory drug; proliferation; apoptosis; gastrointestinal mucosa NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) are commonly prescribed worldwide for patients with arthritis or cardiac and cerebrovascular diseases (16). Upper gastrointestinal (GI) damage is a major adverse effect of NSAID use (16), and, moreover, recent evidence suggests that NSAIDs are responsible for mucosal injury, not only in the upper, but also the lower GI tract (10, 16). Prostaglandin synthesis is considered to play a pivotal role in the mechanism of NSAID-induced GI damage (21); however, its pathophysiology still remains to be elucidated.The regenerating gene (Reg) was originally isolated from rat regenerating pancreatic islet cells, and its human homolog was named REG I␣ (23). Recently, many Reg-related genes have been isolated and shown to constitute a multigene family (types I-IV) (8). We have previously reported that REG I␣ and REG IV are involved in the pathophysiology of GI inflammation (5, 17) and that, moreover, they act as trophic and/or antiapoptotic factors under inflammatory conditions (17, 18). Other investigators have reported that Reg III family genes are overexpressed in inflamed GI mucosa (11,13) and that their products, including REG I␣ and REG IV proteins, may exert trophic and/or antiapoptotic effects on panc...

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Involvement of the IL-22/REG Iα axis in ulcerative colitis

Cited by 75 publications

References 42 publications

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Expression ofRegfamily genes in the gastrointestinal tract of mice treated with indomethacin

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