Involvement of the IL-22/REG Ialpha axis in ulcerative colitis.
The Regenerating gene (REG) Ialpha protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ialpha axis and examined the mechanism of regulation of REG Ialpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ialpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ialpha protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ialpha promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ialpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ialpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ialpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ialpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between -142 and -134 in the REG Ialpha promoter region. REG Ialpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.
Sekikawa
Akira
A
Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan.
Fukui
Hirokazu
H
Suzuki
Katsumasa
K
Karibe
Toyohiko
T
Fujii
Shigehiko
S
Ichikawa
Kazuhito
K
Tomita
Shigeki
S
Imura
Johji
J
Shiratori
Keiko
K
Chiba
Tsutomu
T
Fujimori
Takahiro
T
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D051847:Lithostathine / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D055815:Young Adult; D000097043:Interleukin-22
D048049:Extracellular Signal-Regulated MAP Kinases; D007378:Interleukins; D051847:Lithostathine; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C497617:REG1A protein, human; C494086:STAT3 protein, human; C415369:interleukin-22 receptor