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World J Gastroenterol. Jul 14, 2013; 19(26): 4119-4126
Published online Jul 14, 2013. doi: 10.3748/wjg.v19.i26.4119
Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: Clinico-pathogenic aspects
István Fűri, Ferenc Sipos, Tiana M Germann, Alexandra Kalmár, Zsolt Tulassay, Béla Molnár, Györgyi Műzes
István Fűri, Ferenc Sipos, Alexandra Kalmár, Györgyi Műzes, 2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary
Tiana M Germann, Faculty of Medicine, Semmelweis University, 1086 Budapest, Hungary
Zsolt Tulassay, Béla Molnár, Molecular Medicine Research Unit, Hungarian Academy of Sciences, 1051 Budapest, Hungary
Author contributions: Fűri I, Sipos F and Műzes G contributed to the writing and editing of the manuscript; Germann TM and Kalmár A contributed in figure composing and language editing; Tulassay Z and Molnár B revised the text.
Correspondence to: Ferenc Sipos MD, PhD, 2nd Department of Internal Medicine, Semmelweis University, Szentkirályi str. 46., 1088 Budapest, Hungary.
Telephone: +36-20-4780752 Fax: +36-1-2660816
Received: January 19, 2013
Revised: April 23, 2013
Accepted: April 28, 2013
Published online: July 14, 2013

Toll-like receptors (TLRs) recognize specific motifs which are frequently present in bacteria, fungi, prokaryotes and viruses. Amongst TLRs, TLR9 can be activated by such bacterial or viral DNA fragments, immunoglobulin-DNA complexes or synthetic oligonucleotides, which all contain unmethylated cytosine-guanine nucleotide sequences (CpGs). Emerging data indicate that TLR9 signaling has a role in, and may influence, colorectal carcinogenesis and colonic inflammation. CpGs are classified into three groups according to their influence on both the antigen-specific humoral- and cellular immunity, and the production of type 1 interferons and proinflammatory cytokines. TLR9 activation via CpGs may serve as a new therapeutic target for several cancerous and various inflammatory conditions. Due to its probable anti-cancer effects, the application possibilities of TLR9-signaling modulation may be extremely diverse even in colorectal tumors. In this review we aimed to summarize the current knowledge about TLR-signaling in the pathogenesis and therapy of inflammatory bowel diseases and colorectal cancer. Due to the species-specific differences in TLR9 expression, however, one must be careful in translating the animal model data into the human system, because of the differences between CpG-oligodeoxynucleotide-responsive cells. TLR9 agonist DNA-based immunomodulatory sequences could also represent a promising therapeutic alternative in systemic inflammatory conditions and chronic colonic inflammations as their side effects are not significant.

Keywords: Toll-like receptor 9, Synthetic oligodeoxynucleotide sequences, DNA-based immunomodulatory sequences, Colorectal cancer, Inflammatory bowel diseases

Core tip: Toll-like receptor 9 mediated signaling influences and regulates the severity of mucosal inflammation, and seems to have a protective role against malignant transformation. The modulation of toll-like receptor 9 signaling by synthetic oligodeoxynucleotide agonists or antagonists seems to have beneficial therapeutic effect in inflammatory and cancerous colonic disorders.