Role of the ABCA4 Gene Expression in the Clearance of Toxic Vitamin A Derivatives in Human Hair Follicle Stem Cells and Keratinocytes.

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as "ABCA4-retinopathies." Recent research has revealed that ABCA4 is expressed in other cells as well, such as hair follicles and keratinocytes, although no information on its significance has been evidenced so far. In this study, we investigated the role of the ABCA4 gene in human keratinocytes and hair follicle stem cells for the first time. We have shown that silencing the ABCA4 gene increases the deleterious effect of all-trans-retinal on human hair follicle stem cells.

Peritoneal Fluid from Patients with Ovarian Endometriosis Displays Immunosuppressive Potential and Stimulates Th2 Response.

Endometriosis is a common gynaecological disorder characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is associated with chronic pelvic inflammation and autoimmune reactivity manifesting by autoantibody production and abrogated cellular immune responses. Endometriotic peritoneal fluid contains various infiltrating leucocyte populations and a bulk of proinflammatory and immunoregulatory cytokines. However, the nature and significance of the peritoneal milieu in women with endometriosis still remains obscure. Therefore, the aim of the present study was to investigate the immunoregulatory activity of the peritoneal fluid (PF) from women with endometriosis. The peritoneal fluid samples were collected during laparoscopic surgery from 30 women with and without endometriosis. Immunoregulatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) and chemokines (CCL2, CCL5, CXCL8 and CXCL9) were evaluated in PF and culture supernatants generated by unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells cultured in the presence of PF. The effect of PF on the generation of Treg and Th17 cells in CD4+ T cell cultures, as well as the natural cytotoxic activity of peripheral blood mononuclear cells, was also investigated. Concentrations of IL-6, IL-10, CCL2, CXCL8 and CXCL9 were significantly upregulated in the PF from women with endometriosis when compared to control women, whereas concentrations of other cytokines and chemokines were unaffected. The culturing of unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells in the presence of endometriotic PF resulted in the downregulation of their IL-2, IFN-γ, IL-17A and TNF production as compared to culture medium alone. On the other side, endometriotic PF significantly stimulated the production of IL-4 and IL-10. Endometriotic PF also stimulated the release of CCL2 and CXCL8, whereas the production of CCL5 and CXCL9 was downregulated. Endometriotic PF stimulated the generation of Treg cells and had an inhibitory effect on the generation of Th17 cells in cultures of CD4+ T cells. It also inhibited the NK cell cytotoxic activity of the peripheral blood lymphocytes. These results strongly imply that the PF from patients with endometriosis has immunoregulatory/immunosuppressive activity and shifts the Th1/Th2 cytokine balance toward the Th2 response, which may account for deviation of local and systemic immune responses. However, a similar trend, albeit not a statistically significant one, was also observed in case of PF from women without endometriosis, thus suggesting that peritoneal milieu may in general display some immunoregulatory/immunosuppressive properties. It should be stressed, however, that our present observations were made on a relatively small number of PF samples and further studies are needed to reveal possible mechanism(s) responsible for this phenomenon.

A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes.

Normal cartilage cells are susceptible to lysis by NK cells. This phenomenon may play a role in immune cartilage destruction; however, the mechanisms of chondrocyte recognition by NK cells remain poorly understood. Therefore, the aim of this study was to reveal a possible role of NKR-P1A/lectin-like transcript 1 (LLT1) interaction in NK cell-mediated cytotoxicity against normal human articular chondrocytes. Chondrocytes were isolated from articular cartilage obtained during talonavicular joint surgery. PBMC or polyclonal NK cells isolated from normal donors served as effector cells. Cell-mediated cytotoxicity against chondrocytes was evaluated by means of 18-h 51Cr-release assay. Specific mRNA expression was evaluated by classical and quantitative RT-PCR, and proteins were detected by Western blot analysis. We found that lysis of articular chondrocytes by PBMC or polyclonal NK cells was potentiated by stimulation with IL-2. Stimulation of effector cells with IL-2 downregulated mRNA expression of inhibitory NKR-P1A NK cell receptor, and blocking of NKR-P1A with specific mAbs resulted in increased chondrocyte killing. Chondrocytes constitutively expressed LLT1, a ligand of NKR-P1A. LLT1 expression by chondrocytes could be upregulated by IL-1α and TNF. Chondrocyte treatment with IL-1α resulted in their increased resistance to killing by natural cytotoxic cells. This could be reversed by blocking of NKR-P1A. These results show that susceptibility of normal articular chondrocytes to lysis by NK cells is modulated by NKR-P1A/LLT1 interactions. Thus, NKR-P1A/LLT1 interaction might provide some novel target for therapeutic interventions in the course of pathological cartilage injury.

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction.

BACKGROUND: Despite its established association with chronic kidney disease (CKD) the role of myosin-9 (MYH9) gene variation on transplanted kidney function remains unknown. This study aimed at evaluating the effect of donor MYH9 nephrogenic variants on renal allograft function within the first post transplantation year. METHODS: In the longitudinal kidney transplant study 207 deceased donors were genotyped for previously known risk MYH9 single nucleotide polymorphisms (SNPs). The predictor was MYH9 high-risk variants status. The primary outcome was mean eGFR found in low vs. high risk MYH9 genotypes between third and twelfth post-transplant month, the secondary outcome was the risk of proteinuria. RESULTS: Distribution of genotypes remained in Hardy-Weinberg equilibrium. The T allele of rs3752462 (dominant model, TT or TC vs. CC) was associated with higher filtration rate (P = 0.05) in a multivariate analysis after adjusting for delayed graft function and donor sex. Two G alleles of rs136211 (recessive model, GG vs. GA or AA) resulted in doubling the risk of proteinuria (OR = 2.22; 95% CI = 1.18-4.37, P = 0.017) after adjusting for donor and recipient sex. CONCLUSION: Deceased donor kidneys of European descent harboring MYH9 SNPs rs3752462 T allele show significantly superior estimated filtration rate while those of rs136211 GG genotype excessive risk of proteinuria. These findings, if replicated, may further inform and improve individualization of allocation and treatment policies.

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles.

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

Immunology of alopecia areata.

Alopecia areata is a condition that affects hair follicles and leads to hair loss ranging from small well-defined patches to complete loss of all body hair. Despite its high incidence, the pathobiology is not fully understood, and no single concept could be universally accepted. Alopecia areata is mostly considered to be an autoimmune disease, in which the collapse of hair follicle immune privilege plays a key role. Higher incidence rate in the female population and increased overall risk of other autoimmune disorders militate in favor of autoimmune hypothesis. Antibodies against multiple components of hair follicles almost exclusively attack in anagen phase, where melanogenesis takes place. It suggests involvement of melanogenesis-associated autoantigens as a target epitope. Some investigators believed that alopecia areata is not a truly autoimmune disease but is only 'consistent with' autoimmune mechanisms. High frequency of a positive family history up to 42% may reflects the contribution of heredity factors. In addition, no specific target autoantigen has been identified so far, and autoantibodies to hair follicle-associated antigens are detectable in normal individuals.

Isolation and culture of human primary keratinocytes-a methods review.

Keratinocyte culture is a necessary and widely used tool in a variety of experimental dermatological and biomedical studies. Literature search has revealed a variety of different protocols of human primary keratinocyte isolation and culture. Therefore, the aim of this paper was to review and summarize current trends in human primary keratinocyte culture techniques. We present data on the most popular and effective methods of human keratinocyte isolation and cultivation obtained from screening of 945 papers published during the last 10 years.

Biological and Clinical Significance of Human NKRP1A/LLT1 Receptor/Ligand Interactions.

Killer cell lectin-like receptors (KLRs) are C-type lectin-like glycoproteins encoded by genes clustered in the natural killer gene complex (NKC) located on the short arm of human chromosome 12. In addition to the NKG2 subfamily, the NKC includes a less characterized group of genes coding for NKRP1 receptors and their ligands of the C-type lectin (CLEC) subfamily. Among this group, the best recognized is the NKRP1A/LLT1 pair encoded respectively by the KLRB1 and CLEC2D genes. Both molecules are type II transmembrane-signaling glycoproteins with an extracellular C-type lectin domain. NKRP1A is predominantly expressed on NK cells, where it acts as an inhibitory receptor. However, it stimulates T cells, which results in release of IL-17 and inflammatory cytokines. Triggering LLT1 on NK cells stimulates IFN-γ production. Similarly, it stimulates activation of B cells. LLT1 is also expressed by osteoblasts and chondrocytes and inhibits bone degradation. Expression of LLT1 by tumor cells may facilitate their escape from NK cell surveillance. On the other hand, NKRP1A may be involved in activation of T and B lymphocytes in the course of inflammatory reactions and pathogenesis of autoimmune disorders. Thus, the NKRP1A/LLT1 receptor/ligand system appears to be a new therapeutic target that may be useful in the treatment of cancer as well as some autoinflammatory disorders.

The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis.

Endometriosis is a disease in which endometriotic tissue occurs outside the uterus. Its pathogenesis is still unknown. The most widespread hypothesis claims that ectopic endometrium appears as a result of retrograde menstruation and its insufficient elimination by immunocytes. Some reports have shown expression of non-classical HLA-G molecules on ectopic endometrium. HLA-G is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on natural killer (NK) and other cells. These receptors are polymorphic, which may affect their activity. In this study we investigated whether HLA-G, KIR2DL4, LILRB1 and LILRB2 polymorphisms may influence susceptibility to endometriosis and disease progression. We used polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and allelic discrimination methods with TaqMan SNP Genotyping Assays for typing of 276 patients with endometriosis and 314 healthy fertile women. The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages; HLA-G rs1233334:CT protected against progression; LILRB1 rs41308748:AA and LILRB2 rs383369:AG predisposed to the disease and its progression. No effect of KIR2DL4 polymorphism was observed. These results support the role of polymorphisms of HLA-G and its receptors LILRB1 and LILRB2 in susceptibility to endometriosis and its progression.

[Diet in pathogenesis of acne vulgaris]. / Rola diety w patogenezie tradzika pospolitego.

Acne vulgaris is one of the most common dermatologic condition especially among adolescents. Acne is related to excess sebum production by sebaceous glands, inflammation both within and adjacent to the comedones, hyperproliferation of Propionibacterium acnes. Some of investigations show association between acne and diet. Milk increases the level of IGF-1 leading to the synthesis of androgen-mediated increases sebum production. Chocolate predispose to hyperglycemia and insulinemia which aggravate of acne vulgaris. High levels of omega-6 fatty acids have been associated with increase of acne in contrast to omega-3 fatty acids, which decrease inflammation. Food have huge impact on development and severity of acne and may exert beneficial effect in the treatment of this disorder.

KIR2DS5 in the presence of HLA-C C2 protects against endometriosis.

Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity. Several hypotheses have attempted to explain the etiology and pathogenesis of endometriosis. Recently, it has been suggested that a defect of the natural killer (NK) activity in the recognition and lysis of endometrial cells is one of the crucial points in the development of this disease. Natural killer cells can express killer immunoglobulin-like receptors (KIR), which recognize class I human leukocyte antigens on target cells. We asked whether polymorphisms in KIR, HLA-C, and HLA-B genes are risk factors for endometriosis. We tested 153 women with endometriosis diagnosed on the basis of laparoscopic and histological examination, and 213 control healthy women, who gave birth to at least one child. The frequency of KIR genes in patients was similar to that in controls except for KIR2DS5, which exerted a protective effect only in HLA-C C2-positive individuals. Moreover, KIR2DS5-positive women with endometriosis had 13 times lower chance that the disease would occupy the peritoneum than KIR2DS5- and KIR2DS4del-negative ones (OR = 0.077, P = 0.0061). Similarly, KIR2DS4del-positive endometriotic persons had 11 times lower chance for peritoneal disease (OR = 0.094, P < 0.001). Negative linkage disequilibrium between KIR2DS5 and KIR2DS4del indicates that these genes are mutually exclusive. Our data suggest that KIR2DS5 may be associated with protection from endometriosis, whereas KIR2DS4del seems to be associated with higher disease stages, possibly by exclusion of protective KIR2DS5.

Synthesis of novel, peptidic kinase inhibitors with cytostatic/cytotoxic activity.

The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway.

Constitutive expression of ligand for natural killer cell NKp44 receptor (NKp44L) by normal human articular chondrocytes.

Normal chondrocytes display susceptibility to lysis by natural killer (NK) cells and this phenomenon may play a role in some inflammatory cartilage disorders. The mechanisms of chondrocyte recognition and killing by NK cells remain unclear. Using flow cytometry and immunohistochemical staining we found that normal human articular chondrocytes constitutively express a ligand for NKp44, one of stimulatory NK cell receptors involved in recognition and killing of target cells. Expression of NKp44 ligand by normal articular chondrocytes is not involved in their killing by unstimulated NK cells; however, it is responsible for anti-chondrocyte cytotoxicity mediated by long-term activated NK cells. Thus, expression of NKp44 ligand may play a role in chondrocyte destruction in course of chronic inflammatory cartilage disorders.

CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis.

STUDY QUESTION: Is endometriosis associated with changes in CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells (Treg cells)? SUMMARY ANSWER: Endometriosis is associated with disturbed compartmentalization of CD25(high) FOXP3⁺ Treg cells. WHAT IS KNOWN ALREADY: Endometriosis is associated with an abrogated immune response and displays some features of an autoimmune disorder. Treg cells play a part in the development of autoimmune reactions; however, their role in pathogenesis of endometriosis is still poorly recognized. STUDY DESIGN, SIZE AND DURATION: Case-control study comparing 17 women with laparoscopically and histopathologically confirmed ovarian endometriosis with 15 control women without visible endometriosis foci, pelvic inflammation or related pathology who were subjected to laparoscopic surgery between 2010 and 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Peripheral blood and peritoneal fluid were collected during laparoscopy and T cell subpopulations were analysed by flow cytometry using specific monoclonal antibodies recognizing CD4⁺, CD25⁺ and FOXP3⁺ markers. MAIN RESULTS: The percentage of CD25(high) FOXP3⁺ Treg cells was significantly decreased in the peripheral blood of women with ovarian endometriosis compared with control women. On the other hand, the proportion of these cells was significantly increased in the peritoneal fluid of women with endometriosis. LIMITATIONS, REASONS FOR CAUTION: The present study is limited to patients with ovarian endometrioma and further investigations are needed, including patients with lower grade of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The present results suggest that Treg cells may play a part in immunopathogenesis of endometriosis being responsible for abrogated local cellular immune responses and facilitation and development of autoimmune reactions. Treg cells may be thus a potential target in the treatment of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by 1M15/N/2011 and NK1W grants from the I Faculty of Medicine, Warsaw Medical University. None of the authors has any competing interests to declare.

Proteomic analysis of eutopic and ectopic endometriotic tissues based on isobaric peptide tags for relative and absolute quantification (iTRAQ) method.

OBJECTIVE: The present study aimed at performing proteomic analysis of matched eutopic endometrium and ovarian endometrioid cysts from women with endometriosis in order to discover any abnormal protein expression related to the disease. DESIGN AND SETTING: The study included 8 women with stage III/IV endometriosis according to revised American Fertility Society (rAFS) classification and one woman with no signs of the disease as a reference. Proteomic analysis was performed using a novel isobaric tag-based methodology for relative and absolute peptide quantification (iTRAQ) coupled with multidimensional liquid chromatography and tandem mass spectrometry. RESULTS: The selection of 419 proteins was found in all endometriosis specimens. Using normal eutopic endometrium from woman without endometriosis as a reference, some proteins expressions were significantly increased in all endometriosis samples. They included collagen α1(XIV), calmodulin, collagen α(VI), plexin, integrin αVß3, transgelin, desmin, and vimentin. The comparison of these proteins' expression in paired eutopic and ovarian endometriosis samples has revealed that only vimentin was significantly increased in ovarian endometrioma. CONCLUSIONS: It was confirmed that endometriosis is associated with different expression of proteins in endometriotic samples. Nevertheless, further studies seem to be necessary as they may reveal possible markers that would be useful in clinical diagnosis of the disease.

Fluvastatin influences hair color in C57BL/6 mice.

Our recent in vitro experiments suggest that fluvastatin may influence tyrosinase (key enzyme of melanogenesis) synthesis. The aim of the present study was to verify those findings in experiments, in vitro, in melanoma cell line, and in vivo, in mice. The expression of tyrosinase in B16F10 melanoma cell line, after induction of melanogenesis by UVB irradiation, was examined by Western blot analysis. Afterwards, the effect of fluvastatin on melanin synthesis in hair follicles of C57Bl/6 mice was investigated. The expression of tyrosinase was reduced in the presence of fluvastatin. In mice after anagen induction over the dorsal skin, gel containing fluvastatin in various concentrations was injected subcutaneously, while in part of control groups of mice, gel with placebo was injected. In addition, gel with fluvastatin was injected to four week-old mice (mice in first postnatal anagen) without anagen induction. In extension, injections of gel with fluvastatin or placebo were performed in mice without anagen induction (but after first postnatal anagen). In part of study group of mice (mice after anagen induction and injection of fluvastatin) regrowth of depigmented hair was observed, while in all control groups (mice after injection of placebo), such hair depigmentation over the skin area was not found. In conclusion, this study, for the first time, shows that fluvastatin might affect melanin synthesis in vivo.

[Collagen based dressings in the treatment of wound healing]. / Opatrunki kolagenowe w gojeniu ran.

Collagen is the fundamental protein forming the connective tissues matrix, improves the ability of keratinocytes to migrate to sites that require rebuilding of the damaged epidermis, is one of the component of dressings used to accelerate wound healing. Because of the potential risk of the presence of pathogenic prions in bovine collagen, part of collagen dressings is formed on the basis of porcine collagen. Currently, a least of an immunogenic form of collagen is atelocollagen, which is subjected to enzyme-treated collagen, in which the terminal amino acids are removed from the collagen. It is assumed that in the near future atelocollagen will be used also as a carrier for drugs which support the healing processes.

Expression of ghrelin and its receptors in ovarian endometrioma.

Endometriosis is a common gynaecological disorder manifesting by implantation and growth of endometrial tissue outside the uterine cavity. The evidence accumulates that endometriosis may be associated with abrogated regulation of energy balance. Ghrelin is one of the most important orexigenic factor which may also play a role in regulation of inflammatory and angiogenic reactions. The present study was aimed at investigating expression profile of ghrelin and its receptors (GHSR1α and GHSR1ß) in endometriotic lesions. The study included ovarian cysts and peritoneal fluid specimens obtained laparoscopically from 20 women with revised American Fertility Society stage III or IV endometriosis. Expression of specific mRNAs was assessed by reverse transcription-polymerase chain reaction. Expression of ghrelin and GHSR1α protein was studied by immunohistochemical staining with specific antibodies. Ghrelin and its receptors mRNA expression was found in all tested specimens. Specific mRNAs for these factors were also expressed in the peritoneal leukocytes. Immunohistochemical staining revealed expression of ghrelin and GHSR1α both in glandular endometrioid epithelium and in some stromal cells, particularly in some fibroblasts, blood vessels and infiltrating leukocytes. Co-localization of ghrelin and its receptors strongly suggests that this neuropeptide may affect development and growth of endometriotic lesions and may influence local inflammatory and angiogenic response.

Expression of Fucosyltransferase 4 (FUT4) mRNA Is Increased in Endometrium from Women with Endometriosis.

Endometriosis is a common gynecological disorder defined as the presence of endometrial-like tissue (glands and stroma) outside the uterus. The etiopathogenesis of endometriosis is still poorly recognized. It is speculated that stage-specific embryonic antigen 1 (SSEA-1)-positive stem-like glandular epithelial cells may contribute to the development of the disease. The synthesis of SSEA-1 is mediated by fucosyltransferase 4 encoded by the FUT4 gene. Therefore, this study aimed to evaluate the specific expression of FUT4 mRNA in biopsies of the endometrium from women with and without endometriosis. FUT4 mRNA levels were examined in 49 women with laparoscopically confirmed endometriosis and 28 controls by means of quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The expression of FUT4 mRNA was significantly increased in the endometrium of patients with endometriosis when compared to the controls (p < 0.0001). Expression of FUT4 mRNA in the endometrium was correlated with the severity of endometriosis (rs = 0.5579, p < 0.0001); however, there were no differences in endometrial FUT4 mRNA expression when comparing endometriotic lesions from various locations. The discriminatory ability of FUT4 mRNA expression was evaluated by receiver-operating characteristics (ROC), which showed high statistical significance (AUC = 0.90, p < 0.0001), thus indicating that an increased level of endometrial FUT4 mRNA may serve as a specific marker for endometriosis.

Human papillomavirus type 8 E2 protein unravels JunB/Fra-1 as an activator of the beta4-integrin gene in human keratinocytes.

The papillomavirus life cycle parallels keratinocyte differentiation in stratifying epithelia. We have previously shown that the human papillomavirus type 8 (HPV8) E2 protein downregulates beta4-integrin expression in normal human keratinocytes, which may trigger subsequent differentiation steps. Here, we demonstrate that the DNA binding domain of HPV8 E2 is sufficient to displace a cellular factor from the beta4-integrin promoter. We identified the E2-displaceable factor as activator protein 1 (AP-1), a heteromeric transcription factor with differentiation-specific expression in the epithelium. beta4-Integrin-positive epithelial cells displayed strong AP-1 binding activity. Both AP-1 binding activity and beta4-integrin expression were coregulated during keratinocyte differentiation suggesting the involvement of AP-1 in beta4-integrin expression. In normal human keratinocytes the AP-1 complex was composed of JunB and Fra-1 subunits. Chromatin immunoprecipitation assays confirmed that JunB/Fra-1 proteins interact in vivo with the beta4-integrin promoter and that JunB/Fra-1 promoter occupancy is reduced during keratinocyte differentiation as well as in HPV8 E2 positive keratinocytes. Ectopic expression of the tethered JunB/Fra-1 heterodimer in normal human keratinocytes activated the beta4-integrin promoter, while coexpression of HPV8 E2 reverted the JunB/Fra-1 effect. In summary, we identified a novel mechanism of human beta4-integrin regulation that is specifically targeted by the HPV8 E2 protein mimicking transcriptional conditions of differentiation. This may explain the early steps of how HPV8 commits its host cells to the differentiation process required for the viral life cycle.