Interleukin-5 potentiates the growth response of Caco-2 cells to IGF-II: a role in colonic carcinogenesis complicating ulcerative colitis?
Longstanding ulcerative and Crohn's colitis increases the risk of colorectal cancer (CRC) compared to the general population. Elevated IGF-II mRNA and protein have been found in tumour tissue in sporadic CRC. The association of IGF-II in colitis-related-CRC is unknown.


OBJECTIVE
To determine whether pro-inflammatory cytokines associated with colitis, namely IL-5, TNF-alpha and IL-1beta, alter the proliferative effect of IGF-II on the colorectal cancer cell line, Caco-2.


METHODS
Caco-2 cells were cultured with IGF-II and IL-5, TNF-alpha or IL-1beta. At 24 h intervals cell proliferation was assessed. The mechanism of action of any synergistic affect was investigated by RT-PCR to determine change in mRNA expression of IGF-II, IGF-1R or IGF-2R.


RESULTS
After 72 h, IGF-II increased absorption (corresponding to cell density) compared to controls by 25% (p < 0.02). Co-incubation with IGF-II and IL-5 increased absorption by 42% (p < 0.001) compared to controls and 18% (p < 0.03) compared to IGF-II alone. Enhanced growth response was also seen with TNF-alpha and IL-1beta, but less so than IL-5. The IL-5 receptor was not expressed by Caco-2 cells and mRNA expression of the IGF-1R or IGF-2R was unchanged by incubation with cytokines.


CONCLUSIONS
IGF-II promotes Caco-2 growth, an effect enhanced with IL-5, TNF-alpha and IL-1beta. The greatest response was with IL-5. This was IL-5 receptor-independent. Possible mechanisms include IL-5 interaction on an un-identified receptor or interference with IGF-binding proteins, as occurs with IL-1beta and IL-6. The enhanced growth response of Caco-2 cells to pro-inflammatory cytokines and IGF-II may have implications for the pathogenesis of CRC formation in colitis.
Makins
Richard
R
Centre for Gastroenterology, Barts and the London, Queen Mary's School of Medicine and Dentistry, Turner Street, London E1 2AD, United Kingdom. richardmakins@yahoo.co.uk
Ballinger
Anne
A
D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000150:complications*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015848:Interleukin-5 / Q000494:pharmacology* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D053649:Receptors, Interleukin-5
D015848:Interleukin-5; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1