Ber 13.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptWoodby et al.Pageof a selection of cytokines and chemokines but can be induced to express much more upon stimulation202,203. Cytokine secretion by keratinocytes can differ depending on the anatomical source of the cells202,387. HPV downregulates inflammatory cytokines, chemokines, and downstream pathogen signaling elements in each stimulated and unstimulated cells253. TNF and IL1 are classic inflammatory cytokines that that induce the NFB pathway. IL1 appears to become a central inducer of other cytokines through HPV infections253. Higher grade lesions lack IL1 expression, and E6 is able to prevent IL1 induction388. HPV may also inhibit processing of IL1, which is required for mature cytokine secretion253. E7 confers resistance to growth arrest by TNF389,390. However, HPV may also raise expression of anti-inflammatory cytokines which include TGF (see beneath) and IL10. IL10 mRNA levels are elevated in CIN and expression increases with cancer progression96,391. Expression of IL10 within the stroma is also substantially higher in CIN2 and CIN3 than in typical cervix367,391. HPV can upregulate VEGF (see below) which might be anti-inflammatory, resulting in lowered IL12, DC maturation, and NK T cells, and enhanced Tregs392. Classical tumor suppressor genes inhibited by HPV are HDAC11 Molecular Weight increasingly identified to regulate immune signaling. For instance, loss of p53 or PTEN in either tumor cells or stroma can cause chronic inflammation and persistent tissue damage393. The impact of tumor suppressor loss during HPV infection on immune or inflammatory processes isn’t properly understood. Chemokines are essential for movement of immune cells for the skin (reviewed in304). Chemokines are diffusible molecules, however they can form a gradient by getting immobilized on the ECM304. A variety of chemokines induce directional migration of LCs202, endothelial cells394, and T cells309. Most proinflammatory chemokines increase upon progression to cervical cancer, and some of those, including CXCL1, CXCL2, CXCL5, and CXCL6 are improved in CIN1/2 vs. regular, suggesting direct upregulation by HPV395. IL8, which acts on neutrophils and endothelial cells, is also upregulated207,395. By contrast, E7 suppresses expression of JNK Compound CXCL14 through hypermethylation in the CXCL14 promoter395. CXCL14 is expressed in regular suprabasal epithelial cells and stroma and inhibits angiogenesis by preventing endothelial cell chemotaxis394. CXCL14 may also market chemotaxis of DCs394. Re-expressing CXCL14 in E6/E7-containing cells reduces cell motility and suppresses tumor growth by promoting infiltration of NK cells, CD4+, and CD8+ T cells for the tumor site395. As previously pointed out, the LC-attracting CCL20 is inhibited by HPV308,309. In addition to their effects around the inflammatory and immune atmosphere of a lesion, cytokines can act on HPV containing cells directly: TNF, IL1, IL-4, and TGF1 can inhibit HPV transcriptional activity within a dose-dependent manner98,396. The impact of this impact on HPV in vivo will not be clear.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptProg Mol Biol Transl Sci. Author manuscript; obtainable in PMC 2017 December 13.Woodby et al.Page6.4.2. Immune functions of TGF–TGF acts as a cytokine to regulate immune function during both innate and adaptive responses393. Innate immunity: TGF is antagonistic to kind I and variety II IFN responses. Epithelia (but not macrophages) treated with TGF are less.
