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Cervical squamous carcinoma cells are resistant to the combined action of tumor necrosis factor-α and histamine whereas normal keratinocytes undergo cytolysis

Nicolae-Costin Diaconu1*, Jaana Rummukainen2, Mikko Mättö3, Anita Naukkarinen2, Rauno J Harvima1, Jukka Pelkonen3 and Ilkka T Harvima1

Author Affiliations

1 Department of Dermatology, University of Kuopio, Kuopio, Finland

2 Department of Pathology, Kuopio University Hospital, Kuopio, Finland

3 Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland

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BMC Cancer 2008, 8:46  doi:10.1186/1471-2407-8-46

Published: 7 February 2008



Previous reports showed that mast cells can typically be found in the peritumoral stroma of cervix carcinomas as well as in many other cancers. Both histamine and TNF-α are potent preformed mast cell mediators and they can act simultaneously after release from mast cells. Thus, the effect of TNF-α and histamine on cervical carcinoma cell lines was studied.

Methods and results

TNF-α alone induced slight growth inhibition and cell cycle arrest at G0/G1 phase in SiHa cells, but increased their migration. Histamine alone had no effect on cells. In addition, TNF-α and histamine in combination showed no additional effect over that by TNF-α alone, although SiHa cells were even pretreated with a protein synthesis inhibitor. Furthermore, TNF-α-sensitive ME-180 carcinoma cells were also resistant to the combination effect of TNF-α and histamine. In comparison, TNF-α or histamine alone induced growth inhibition in a non-cytolytic manner in normal keratinocytes, an effect that was further enhanced to cell cytolysis when both mediators acted in combination. Keratinocytes displayed strong TNF receptor (TNFR) I and II immunoreactivity, whereas SiHa and ME-180 cells did not. Furthermore, cervix carcinoma specimens revealed TNF-α immunoreactivity in peritumoral cells and carcinoma cells. However, the immunoreactivity of both TNFRs was less intense in carcinoma cells than that in epithelial cells in cervical specimens with non-specific inflammatory changes.


SiHa and ME-180 cells are resistant to the cytolytic effect of TNF-α and histamine whereas normal keratinocytes undergo cytolysis, possibly due to the smaller amount of TNFRs in SiHa and ME-180 cells. In the cervix carcinoma, the malignant cells may resist this endogenous cytolytic action and TNF-α could even enhance carcinoma cell migration.