Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma.
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.
Poutahidis
Theofilos
T
Division of Comparative Medicine.
Haigis
Kevin M
KM
Rao
Varada P
VP
Nambiar
Prashant R
PR
Taylor
Christie L
CL
Ge
Zhongming
Z
Watanabe
Koichiro
K
Davidson
Anne
A
Horwitz
Bruce H
BH
Fox
James G
JG
Erdman
Susan E
SE
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
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D016753:Interleukin-10