Interferon-beta and -gamma, but not tumor necrosis factor-alpha, demonstrate immunoregulatory effects on carcinoma cell lines infected with human papillomavirus.
BACKGROUND
Mechanisms whereby cells infected with human papillomavirus (HPV) escape immune surveillance, ultimately leading to invasive cervical carcinoma, may involve changes in local cytokine production, loss of responsiveness to cytokines, and alterations in the expression of immune-regulatory molecules such as histocompatibility-related leukocyte antigen (HLA) Class 1 and 2 and ICAM-I. This study examined the separate and combined effects of immune-activating cytokines, interferon (IFN)-gamma, IFN-beta, and tumor necrosis factor (TNF)-alpha, on the expression of these molecules.


METHODS
Membrane protein expression and cellular mRNA levels were analyzed in cervical carcinoma-derived cell lines, SiHa and CaSki (with low and high HPV16 copy number, respectively), after exposure to cytokines.


RESULTS
Both cell lines demonstrated constitutive expression of HLA Class 1 but not HLA Class 2 membrane antigens. IFN-gamma and -beta induced changes in Class 1 mRNA levels but not in membrane molecule expression. IFN-gamma induced dose-dependent expression of Class 2 membrane and mRNA molecules in both cell lines (more pronounced in SiHa than in CaSki cells), which was antagonized by IFN-beta. Constitutive ICAM-I membrane expression was observed only on CaSki cells, although ICAM-I mRNA was expressed in both cell lines. IFN-gamma up-regulated the membrane expression of this molecule, whereas IFN-beta led to its suppression. Differential modulation of ICAM-I mRNA was observed in both cell lines. A lack of response to TNF-alpha was observed throughout the experiments.


CONCLUSIONS
The findings of this study point to possible mechanisms leading to suppression of local immune response in the pathogenesis of HPV-associated neoplasia. They also emphasize the complexity of developing an efficient cytokine therapy for patients with premalignant cervical disease.
Bornstein
J
J
Department of Obstetrics and Gynecology, Lady Davis Carmel Medical Center, Haifa, Israel.
Lahat
N
N
Kinarty
A
A
Revel
M
M
Abramovici
H
H
Shapiro
S
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000276:immunology / Q000821:virology*
D000276:Adjuvants, Immunologic; D006680:HLA Antigens; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D007371:Interferon-gamma