Expression of membrane type 1 matrix metalloproteinase in papillomavirus-positive cells: role of the human papillomavirus (HPV) 16 and HPV8 E7 gene products.

Matrix metalloproteinases (MMPs) degrade extracellular matrix. They are involved in cellular proliferation, migration, angiogenesis, invasion and metastasis. MT-1 MMP, a membrane-bound MMP, is expressed in carcinomas of the uterine cervix in vivo. This type of cancer is associated with human papillomavirus (HPV) infection. Here it was shown that keratinocytes transformed with HPV16 or HPV18 in vitro, and HPV-positive cervical carcinoma cell lines, constitutively expressed MT-1 MMP. Expression of the E7 protein from the mucosal and cutaneous high-risk types HPV16 and HPV8, but not from the cutaneous low-risk type HPV1, was sufficient to induce MT-1 MMP expression in primary human keratinocytes and HaCaT cells. As a consequence, MMP-2 was activated. MT-1 MMP expression might play a role in the HPV life cycle by promoting proliferation of host cells and might contribute to their invasive phenotype during malignant progression.

Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression.

Interleukin-6 (IL-6) is produced during bacterial and viral infections and by various malignant tumors. Here, we describe novel immunosuppressive properties of IL-6 in dendritic cells (DC). In the presence of GM-CSF, IL-4, and a maturation stimulus, IL-6 skewed monocyte differentiation into phenotypically mature but functionally impaired DC. In DC matured with the toll-like receptor (TLR)4 stimulus lipopolysaccharide (LPS) or other pro-inflammatory stimuli, IL-6 inhibited CCR7 chemokine receptor up-regulation. As demonstrated for LPS-stimulated DC, IL-6 impaired chemotaxis to CCR7-activating chemokines required for recruiting DC to lymphoid tissues in vivo. Moreover, IL-6 inhibited production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma inducible protein-10 (IP-10) in DC, and DC-driven allogeneic T cell proliferation in mixed lymphocyte reactions. CCR7 expression was blocked at the transcriptional level. IL-6 led to inhibition of nuclear factor-kappaB (NF-kappaB) binding activity, regulating CCR7 transcription. Neutralization experiments revealed that autocrine IL-10 partially contributed to CCR7 suppression in IL-6-treated DC. Thus IL-6, a cytokine once labeled as "pro-inflammatory" can mediate immunosuppressive functions, which may involve induction of the classical "anti-inflammatory" cytokine IL-10. Because IL-6 is expressed in response to various pro-inflammatory stimuli in vivo, this mechanism may contribute to down-regulating the immune response initiated by pathogens, in persistent infections or tumors.