DMBT1 is a novel gene induced by IL-22 in ulcerative colitis.
BACKGROUND
Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation.


METHODS
Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si)RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-κB). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.


RESULTS
IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-κB activation in colon cancer cells. The IL-22-responsive element was located between -187 and -179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium.


CONCLUSIONS
The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC.
Fukui
Hirokazu
H
Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan.
Sekikawa
Akira
A
Tanaka
Hiroyuki
H
Fujimori
Yukari
Y
Katake
Yoshinori
Y
Fujii
Shigehiko
S
Ichikawa
Kazuhito
K
Tomita
Shigeki
S
Imura
Johji
J
Chiba
Tsutomu
T
Fujimori
Takahiro
T
D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology*; D018123:Receptors, Interleukin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D025521:Tumor Suppressor Proteins; D000097043:Interleukin-22
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D007378:Interleukins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D025521:Tumor Suppressor Proteins; D000097043:Interleukin-22; C108174:DMBT1 protein, human; C494086:STAT3 protein, human; C415369:interleukin-22 receptor