title: Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma.
abstract: Chronic inflammation of mucosal surfaces renders them increasingly susceptible to epithelial cancers both in humans and mice. We have previously shown that anti-inflammatory CD4(+)CD45RB(lo)CD25(+) regulatory (Treg or T(R)) lymphocytes down-regulate inflammation and block development of bacteria-triggered colitis and colorectal cancer (CRC) in 129/SvEv Rag2-/- mice. Interestingly, T(R) cells collected from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma with a strong gender bias expressing in male mice. We found we show that peritoneal invasion in this model is dependent on pleiotropic cytokine IL-6. Mucinous carcinoma arose rapidly and consistently after treatment with IL10-/- T(R) cells, which were found to express Foxp3+ and localize throughout tumor tissue. Carcinogenesis was rapidly reversible with transfer of wild type IL10-competent T(R) cells. Likewise, treatment with IL10-Ig fusion protein was sufficient to revert the lesions histologically, and restore inflammatory cytokine and oncogene expression to base line levels. These studies indicate an essential role for IL 6 in this CRC phenotype. Furthermore, immune-competent T(R) cells were important not only for preventing pathology but also for constructive remodeling of bowel following tumorigenic microbial insults. These data provide insights into etiopathogenesis of inflammation-associated epithelial invasion and maintenance of epithelial homeostasis.
authors.affiliation: Division of Comparative Medicine.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Varada P
authors.initials: VP
authors.lastname: Rao
authors.forename: Prashant R
authors.initials: PR
authors.lastname: Nambiar
authors.forename: Christie L
authors.initials: CL
authors.lastname: Taylor
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.forename: Koichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D003092:Colitis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D044923:Helicobacter hepaticus; D016753:Interleukin-10 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D016753:Interleukin-10