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Biomedical subjects

Michele Mondini

Publications and source records attributed to Michele Mondini.

5 recordsLinked to original sources
PubMed2006

Alpha- and betapapillomavirus E6/E7 genes differentially modulate pro-inflammatory gene expression.

Keratinocytes, the target cell of human papillomavirus (HPV) infection, can produce numerous cytokines and pro-inflammatory molecules which are important for the generation of an effective immune response. How this biological response, which involves the tumor stroma, is affected by the HPV oncoproteins within the epithelial cell itself is not clear. Here it is shown that oncoproteins of different HPV genotypes (alpha- versus beta-HPV genus) alter the expression of pro-inflammatory molecules in early passage primary human keratinocytes and the immortalized cell line HaCaT. HPV5 E6/E7 oncoproteins significantly induced interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) expression. By contrast, the same molecules were down-regulated or not modulated in HPV16 E6/E7 transduced keratinocytes. Interestingly, HPV38 oncoproteins expression resulted in a lower induction of pro-inflammatory molecules, resembling the behavior displayed by the mucosal carcinogenic HPV16. Finally, inducible nitric oxide synthase (iNOS) expression levels and nitric oxide (NO) production were induced at similar levels by all the HPV genotypes tested. These results further emphasize the different biological activities among HPV genotypes, and offer new insights into HPV-associated skin diseases.

Alphapapillomavirus↗
PubMed2006

The expression of p16INK4a tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication.

The human cytomegalovirus (HCMV) induces a replicative senescence program after arresting host cell cycle progression so as to create a favorable environment for its replication. Here, we report that HCMV infection stimulates the expression of p16(INK4a), a direct effector of the senescence phenotype. The increase in p16(INK4a) gene expression was due to an increase in gene transcription, since the expression of a reporter gene driven by the p16(INK4a)-encoding CDKN2A gene promoter was strongly induced by HCMV infection. The results of deletion and mutational analysis of the CDKN2A promoter further suggest the involvement of Ets transcription factors in HCMV-mediated stimulation of p16(INK4a) gene expression. The significance of p16(INK4a) upregulation during the HCMV replicative cycle is underscored by the finding that virus replication was severely impaired in fibroblasts homozygous for an intragenic deletion in CDKN2A locus and devoid of functional p16(INK4a). Moreover, a retrovirus-mediated p16(INK4a) small interfering RNA (p16-siRNA) effectively reduced viral replication, thus providing direct evidence that p16(INK4a) upregulation plays a positive role for HCMV replication.

Artificial Gene Fusion↗
PubMed2006

A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cutaneous systemic sclerosis: the interferon-inducible gene IFI16.

OBJECTIVE: To investigate the presence and clinical significance of autoantibodies against the interferon-inducible gene IFI16 in systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and other autoimmune diseases. METHODS: Immunohistochemical analysis was used to evaluate the expression of IFI16 in skin biopsy specimens obtained from patients with SSc and patients with SLE. Levels of antibodies against IFI16 in sera from 82 patients with SSc and 100 patients with SLE were determined by enzyme-linked immunosorbent assay. Other autoimmune diseases such as primary Sjögren's syndrome (SS), rheumatoid arthritis (RA), chronic urticaria, and hepatitis C virus (HCV) infection were also examined. RESULTS: Expression of IFI16 was greatly increased and was ubiquitous in all layers of the epidermis and in the dermal inflammatory infiltrates of lesional skin from both patients with SLE and patients with SSc. Patients with SLE, those with primary SS, and those with SSc exhibited significantly higher anti-IFI16 IgG antibody levels compared with normal controls (for SLE, P < 0.002; for primary SS, P < 0.001; for SSc, P < 0.0005). Anti-IFI16 titers above the ninety-fifth percentile for control subjects were observed in 26% of the patients with SLE, 50% of those with primary SS, and 21% of those with SSc (28% of patients with limited cutaneous SSc [lcSSc] versus 4% of patients with diffuse cutaneous SSc [dcSSc]). In contrast, the prevalence of anti-IFI16 was 4% in patients with RA, 5% in those with chronic urticaria, and 13% in those with HCV infection. CONCLUSION: The results of this study provide evidence that an IFN-inducible gene, IFI16, may be involved in the pathophysiologic mechanisms of connective tissue disorders such as SSc. Moreover, a strict correlation with lcSSc was also demonstrated, thus providing a novel tool in the differential diagnosis of lcSSc from dcSSc.

Adult↗
PubMed2005

Up-regulation of the interferon-inducible IFI16 gene by oxidative stress triggers p53 transcriptional activity in endothelial cells.

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), induces injury of endothelium in a variety of pathophysiological conditions, such as inflammation, aging, and cancer. In our study, we characterized the signaling pathway linking oxidative stress induced by sublethal concentrations of H2O2 to p53 in primary human endothelial cells through the interferon (IFN)-inducible gene IFI16. Induction of IFI16 by H2O2 was concentration- and time-dependent (maximum at 50 microM, 6 h after treatment) and down-regulated by pretreatment with N-acetyl-L-cysteine, which acts as an antioxidant. This pathway is a general response to ROS and not specific to H2O2 treatment, as two other ROS-generating compounds, i.e., S-nitroso-N-acetylpenicillamine and tert-butyl hydroperoxide, were equally capable to induce IFI16. Moreover, IFI16 up-regulation is a result of protein accumulation, as expression of corresponding mRNA, assessed by real-time polymerase chain reaction, was not affected. To investigate the mechanism of IFI16 accumulation, cells were incubated for 6 h in the presence of H2O2 or IFN-beta, and then cycloheximide was added to inhibit further protein synthesis. The half-life of IFI16 protein was found to be significantly increased in H2O2-treated cells compared with IFN-beta-treated cells (t1/2 = 120 min vs. > 30 min in H2O2- vs. IFN-beta-treated cells, respectively). An increase of IFI16 was accompanied by interaction with p53 phosphorylated at its N terminus, as shown by immunoprecipitation experiments. Moreover, binding to IFI16 resulted in its transcriptional activation as shown by an increase in the activity of a reporter gene driven by p53-responsive sequences derived from the p21(WAF1) promoter, along with an increase in the p21 mRNA and protein levels. Altogether, these results demonstrate a novel role of IFI16 in the signal transduction pathway that leads to p53 activation by oxidative stress in endothelial cells.

Cell Cycle Proteins↗