Abstract
BackgroundNatural killer (NK) cells are an important resource of the innate immune system directly involved in the spontaneous recognition and lysis of virus-infected and tumor cells. An exquisite balance of inhibitory and activating receptors tightly controls the NK cell activity. At present, one of the best-characterized activating receptors is NKG2D, which promotes the NK-mediated lysis of target cells by binding to a family of cell surface ligands encoded by the MHC class I chain-related (MIC) genes, among others. The goal of this study was to describe the expression pattern of MICA and MICB at the molecular and cellular levels in human cervical cancer cell lines infected or not with human papillomavirus, as well as in a non-tumorigenic keratinocyte cell line.ResultsHere we show that MICA and MICB exhibit differential expression patterns among HPV-infected (SiHa and HeLa) and non-infected cell lines (C33-A, a tumor cell line, and HaCaT, an immortalized keratinocyte cell line). Cell surface expression of MICA was higher than cell surface expression of MICB in the HPV-positive cell lines; in contrast, HPV-negative cells expressed lower levels of MICA. Interestingly, the MICA levels observed in C33-A cells were overcome by significantly higher MICB expression. Also, all cell lines released higher amounts of soluble MICB than of soluble MICA into the cell culture supernatant, although this was most pronounced in C33-A cells. Additionally, Real-Time PCR analysis demonstrated that MICA was strongly upregulated after genotoxic stress.ConclusionsThis study provides evidence that even when MICA and MICB share a high degree of homology at both genomic and protein levels, differential regulation of their expression and cell surface appearance might be occurring in cervical cancer-derived cells.
Highlights
Natural killer (NK) cells are an important resource of the innate immune system directly involved in the spontaneous recognition and lysis of virus-infected and tumor cells
Despite the fact that MICA and MICB share a high homology at the DNA and protein level, there is evidence for differential regulation of their promoters [25] indicating that these molecules could respond dissimilarly to several damage stimuli
In order to elucidate this point, we addressed cell surface expression of MICA/B in various established cervical tumor cell lines known to be infected with human papillomavirus (HPV)-18 (HeLa), HPV-16 (SiHa) or uninfected (C33-A)
Summary
Natural killer (NK) cells are an important resource of the innate immune system directly involved in the spontaneous recognition and lysis of virus-infected and tumor cells. NK cells are major innate effectors for the early recognition of transformed cells because they can spontaneously detect their targets (ULBPs) 1 to 5, originally identified through interactions with the cytomegalovirus UL16 glycoprotein. Both MIC and ULBP proteins engage NKG2D, which triggers the cytokine production and cytotoxic activity seen in activated NK cells [7,8,9,10,11]. Despite the fact that MICA and MICB share a high homology at the DNA and protein level, there is evidence for differential regulation of their promoters [25] indicating that these molecules could respond dissimilarly to several damage stimuli
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