Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts.
OBJECTIVE
Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs).


METHODS
Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs).


RESULTS
IL-22 was not detectable in normal colonic mucosa. In IBD mucosa, IL-22 expression was detectable in CD4-positive T cells. IL-22-positive cells were increased in ulcerative colitis and even more so in Crohn's disease. IL-22 receptor expression colocalized with a marker of SEMFs. IL-22 did not modulate SEMF proliferation and collagen synthesis. cDNA microarray analyses demonstrated that, in colonic SEMFs, IL-22 increased the messenger RNA (mRNA) expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor [LIF]), chemokines, and matrix metalloproteinases. IL-22 induced an activation of nuclear factor (NF)-kappaB and activating protein (AP)-1 within 1 hour, and a blockade of NF-kappaB and AP-1 activation markedly reduced IL-22 induction of IL-6, IL-8, IL-11, and LIF mRNA. MAP-kinase inhibitors (PD98059, U0216, and SB202190) significantly reduced IL-22 induction of cytokine secretion. The combination of either IL-17 plus IL-22 or IL-19 plus IL-22 additively up-regulated cytokine secretion.


CONCLUSIONS
IL-22 derived from activated T cells acts on SEMFs to elicit expression of proinflammatory cytokines and matrix-degrading molecules indicating proinflammatory/remodeling roles in IBD.
Andoh
Akira
A
Department of Internal Medicine, Shiga University of Medical Science, Seta Tukinowa, Otsu, Japan. andoh@belle.shiga-med.ac.jp
Zhang
Zhuobin
Z
Inatomi
Osamu
O
Fujino
Sanae
S
Deguchi
Yasuyuki
Y
Araki
Yoshio
Y
Tsujikawa
Tomoyuki
T
Kitoh
Katsuyuki
K
Kim-Mitsuyama
Shokei
S
Takayanagi
Atsushi
A
Shimizu
Nobuyoshi
N
Fujiyama
Yoshihide
Y
D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D007378:Interleukins / Q000235:genetics* / Q000494:pharmacology* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D000097043:Interleukin-22
D016207:Cytokines; D007378:Interleukins; D000097043:Interleukin-22