transforming-growth-factor-beta and Lichen-Planus--Oral

Cytokines are powerful mediators which play a central role in both innate and adapted immune responses. Aberrant productions of cytokines may lead to the onset of immune deficiency, allergy or autoimmunity, which are involved in the mechanisms of various immune-mediated inflammatory diseases. Oral lichen planus (OLP) is a chronic inflammation disease affecting the oral mucosa with unknown aetiology. Previous studies have described the abnormal expression patterns of various inflammation-related cytokines, such as IL-1, 2, 4, 5, 6, 8, 10, 12, 17, 18, TGF-β, IFN-γ and TNF-α, in lesions, saliva, serum and peripheral blood mononuclear cells from patients with OLP, which may reflect the immune dysregulation status and emerge as central players in the immunopathogenesis of OLP. Besides, the gene polymorphisms of several cytokines such as IFN-γ, TNF-α, IL-4, IL-10 have been found to be involved in the susceptibility of OLP. In this review, we gave a brief introduction of the characteristics and biological functions of these inflammation-related cytokines and summarized for the first time the current knowledge on the involvement of inflammation-related cytokines in OLP. Further research on the exact roles of these cytokines will aid the understanding of the pathogenesis and the identification of novel therapeutic approaches of OLP.

Topics: Cytokines; Genetic Predisposition to Disease; Humans; Inflammation Mediators; Interferon-gamma; Interleukins; Lichen Planus, Oral; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Oral Potentially Malignant Disorders (OPMDs) including Oral Lichen Planus (OLP) are associated with risk of transformation to oral squamous cell carcinoma (OSCC). Available data show that innate immune cells involving polymorphonuclear neutrophils (PMNs) with their ability to neutrophil extracellular traps (NETs) formation are likely to be directly involved in development of cancer. Examination of NETs generation by TGF-β - induced neutrophils of OLP patients showed increased amounts of traps with MPO, H3Cit and cfDNA, known to be released with NETs. The presence of excessive amounts of NETs components may lead to numerous adverse consequences associated with potential transformation to OSCC. Bacterial-related infection may enhance the NETs formation and lead to consequences resulting from the excessive number of individual elements of these networks. It is likely that regulating NETs release by the flavonoids presented herein may be beneficial not only for inhibiting OLP development, but also in reducing risk of transformation to OSCC.

Topics: Cell Transformation, Neoplastic; Extracellular Traps; Female; Humans; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Neutrophils; Squamous Cell Carcinoma of Head and Neck; Transforming Growth Factor beta

We sought to investigate the expression of cells with immunosuppressive/protumorigenic phenotypes in oral lichen planus (OLP), such as M2-tumor-associated macrophages (TAM2), myeloid-derived suppressive cells (MDSCs), and regulatory T cells (Tregs) in association with clinical parameters.. Cases of hyperkeratotic (HK)-OLP (n = 23) and erosive (E)-OLP (n = 26) were immunohistochemically stained to determine the percentages of CD163-TAM2, CD80-MDSCs, and FOXP3-Tregs of proinflammatory CD121a-Th17, CD4 and CD8 lymphocytes, and of cells positive for nuclear factor kappa B (NF-κB) and transforming growth factor beta. Clinical parameters included symptoms, treatment approach, treatment response, and others.. The inflammatory infiltrate in HK-OLP and E-OLP contained immunosuppressive cells; however, their pattern of expression was compatible with a proinflammatory response [membranous CD163-TAM2 staining (not extracellular), CD80+ lymphocytes (not macrophages), and a few Tregs]. The presence of CD4+, CD8+, and CD121a+ T lymphocytes was extensive. TAM2 were more frequent in E-OLP than in HK-OLP (P = 0.017). A higher frequency of CD80+ lymphocytes was associated with partial to no response to treatment (P = 0.028). Nuclear expression of NF-κB in the inflammatory cells was absent.. The pattern of expression of the immunosuppressive cells, together with numerous CD4+, CD8+, and Th17-CD121a+ lymphocytes, suggest an extensive proinflammatory response rather than an immunosuppressive/protumorigenic response.. The frequency of selective types of inflammatory cells calls for individual profile analyses of inflammatory infiltrates and individually adjusted treatment.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-1 Antigen; Female; Humans; Immune Tolerance; Inflammation; Lichen Planus, Oral; Macrophages; Male; Middle Aged; NF-kappa B; Phenotype; Receptors, Cell Surface; Suppressor Factors, Immunologic; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa which the World Health Organisation (WHO) considers a premalignant condition. One step in malignant development is so called epithelial mesenchymal transition (EMT), a process whereby epithelial cells acquire mesenchymal characteristics. EMT occurs during embryogenesis and wound healing but also in some human diseases such as cancer and fibrosis. A factor known to induce EMT is transforming growth factor-β (TGF-β), which uses the Smad proteins as mediators for its signalling. TGF-β is also often over-expressed in squamous cell carcinoma of the head and neck (SCCHN).. In the present study we mapped expression of Smad proteins in OLP lesions by immunohistochemistry, and compared to expression in normal and sensitive oral mucosa. The latter group of patients had developed SCCHN after shorter or longer periods of diffuse oral symptoms. The aim was to see if there were any signs of EMT related changes in the OLP lesions, as judged by changes in the TGF-β pathway.. Changes in the TGF-β pathway related to EMT are seen in the very earliest stages of oral malignancy and become more severe as lesions progress.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Disease Progression; Epithelial-Mesenchymal Transition; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lichen Planus, Oral; Male; Middle Aged; Mouth Mucosa; Precancerous Conditions; Smad Proteins; Smad2 Protein; Smad3 Protein; Smad4 Protein; Smad7 Protein; Transforming Growth Factor beta; Young Adult

Matrix metalloproteinases (MMPs) and transforming growth factor-beta1 (TGF-beta1) are important in many physiological and pathological processes.. Immunohistochemistry for MMP-2, MMP-9, membrane-type 1 MMP (MT1-MMP, MMP-14), tissue inhibitor of matrix metalloproteinase (TIMP)-2, and TGF-beta were performed on normal mucosa, nonatrophic oral lichen planus, atrophic oral lichen planus, and oral squamous cell carcinomas (OSCC) resulting from lichen planus.. Expression of MMPs progressively increased from normal mucosa to nonatrophic oral lichen planus, atrophic oral lichen planus, and OSCCs. Immunoscores of MMPs in atrophic oral lichen planus was significantly greater than nonatrophic oral lichen planus. Moreover, immunoscore of MMP-9 of OSCCs was significantly greater than both atrophic and nonatrophic lichen planus. Furthermore, expression of TIMP-2 and TGF-beta1 paralleled increases seen with MMPs.. Imbalance between MMPs and TIMPs may be involved in cancerization of oral lichen planus. MMP-2, MT1-MMP, and especially MMP-9 may be useful markers for judging potency of malignant transformation from oral lichen planus.

Topics: Adult; Age Factors; Biomarkers, Tumor; Biopsy, Needle; Case-Control Studies; Cell Transformation, Neoplastic; Cytokines; Disease Progression; Female; Humans; Immunohistochemistry; Lichen Planus, Oral; Male; Metalloproteases; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Probability; Prognosis; Reference Values; Retrospective Studies; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Sex Factors; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Bone morphogenic protein (BMP-4) is a member of transforming growth factor (TGF-beta) family and involved in various functions including apoptosis during neural ectoderm development. The objective of this study is to determine whether BMP-4 is involved in apoptosis, one characteristic, of human oral lichen planus (OLP).. Immunohistochemistry and in situ hybridization for BMP-4 were carried out in OLP (n = 21) and normal human oral mucosa (NOM, n = 31). Five tissue samples from NOM and OLP were underwent reverse transcriptase-polymerase chain reaction (RT-PCR). In vitro organ culture of oral mucosa was carried out with beads soaked with various concentration of BMP-4 (0.1, 1, and 10 microg/ml). The samples from in vitro organ culture were undergone haematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling technique (TUNEL) assay, and immunohistochemical study with p53, matrix metalloproteinases (MMP)-1, and MMP-3. Involucrin expression was determined by western blot analysis after treatment with BMP-4 or TGF-beta1 on human oral keratinocytes.. In immunohistochemical analysis, expression of BMP-4 was higher in OLP than NOM. BMP-4 mRNA expression was also detected in epithelial cells of both NOM and OLP together with underlying T-lymphocytes by in situ hybridization and RT-PCR. In oral mucosa organ culture, BMP-4 soaked beads induced apoptosis of epithelial cells. Acantolysis combined with apoptosis in oral epithelium was observed at 1 microg/ml of BMP-4 beads and it was due in part to the induction of p53 and MMP-1. Even MMP-3 induction was found in lower concentration of BMP-4 (0.1 and 1 microg/ml). Moreover, the expression of MMP-1 and MMP-3 was also observed in OLP. Recombinant BMP-4 or TGF-beta1 increased involucrin expression in human oral keratinocytes cell line.. Expression of BMP-4 of epithelial cells was higher in OLP than NOM. High concentration of BMP-4 caused an apoptosis of oral epithelial cells in oral mucosa organ culture. Therefore, over-expression of BMP-4 is one causing factor for apoptosis of oral epithelial cells through upregulation of p53, MMP1 and MMP3 in OLP.

Topics: Adult; Apoptosis; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cells, Cultured; DNA Fragmentation; Epithelial Cells; Female; Humans; Keratinocytes; Lichen Planus, Oral; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Middle Aged; Mouth Mucosa; Organ Culture Techniques; Protein Precursors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Protein p53; Up-Regulation

Lichen planus (LP) is a chronic common mucocutaneous inflammatory disorder of uncertain aetiology. An association between hepatitis C virus (HCV) infection and LP has been recognised, particularly in Italy, Spain and Japan. The pathogenesis of such an association is unclear, but it may be due to cell-mediated cytotoxicity to an epitope shared by HCV and damaged keratinocytes. Recent studies using in situ hybridization suggest that HCV may replicate in the oral mucosa.. The aim of the present study was to examine the oral epithelium of patients with oral LP for evidence of HCV-RNA by polymerase chain reaction (PCR) and to examine the relationship to cytokines including interferon (INF-gamma), interleukins (IL-1, IL-2, IL-4, IL-6, IL-8 , and IL-10), tumour necrosis factor (TNF-alpha) and transforming growth factor (TGFbeta-1).. We selected 100 Italian patients, and divided them into 4 groups. Group A consisted of 25 HCV+ve patients with erosive oral LP. Group B was a control group constituted by 25 healthy HCV -ve subjects with no LP. Group C consisted of 25 HCV-ve patients with oral reticular LP and Group D was made of 25 HCV-ve patients with oral erosive LP. The patients of group A (test group) were submitted to oral biopsy with 2 samples of epithelium, lesional and non-lesional, and a 10 ml peripheral blood sample was taken. The patients of group B (negative control), C and D (comparison groups) were submitted to oral epithelial biopsy and a 10 ml peripheral blood sample was collected. PCR was used to search for HCV-RNA in biopsy material. Cytokines INF-gamma ,IL-1, IL-2, IL-4, IL-6, IL-8 , IL-10 and TNF-alpha and TGFbeta-1 were assayed in serum.. PCR did not detect the viral genome in oral epithelium of the patients with oral LP and HCV+ve (group A), but there was an increase in levels of TNF-alpha and a reduction of IL-1, INF-gamma and IL-8 compared to patients who had oral reticular LP but HCV-ve and to patients who had oral erosive LP but HCV-ve, and compared to negative controls. The results indicate that patients of group A showed a reduction of pro-inflammatory but an increase in immunomodulant cytokines. The results suggest the possibility that HCV exerts an indirect effect, mediated possibly by the induction of cytokines and lymphokines.

Topics: Cytokines; Female; Hepacivirus; Hepatitis C Antibodies; Hepatitis C, Chronic; Humans; Interferon-gamma; Interleukins; Keratinocytes; Lichen Planus, Oral; Male; Mouth Mucosa; Polymerase Chain Reaction; RNA, Viral; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Cell-mediated immune responses in oral lichen planus (OLP) may be regulated by cytokines and their receptors.. In situ cytokine expression and in vitro cytokine secretion in OLP were determined by immunohistochemistry and ELISA.. The majority of subepithelial and intraepithelial mononuclear cells in OLP were CD8+. In some cases, intraepithelial CD8+ cells were adjacent to degenerating keratinocytes. CD4+ cells were observed mainly in the deep lamina propria with occasional CD4+ cells close to basal keratinocytes. Mononuclear cells expressed IFN-gamma in the superficial lamina propria and TNF-alpha adjacent to basal keratinocytes. Basal keratinocytes expressed TNF-alpha as a continuous band. TNF R1 was expressed by mononuclear cells and basal and suprabasal keratinocytes. There was variable expression of TGF-beta1 in the subepithelial infiltrate while all intraepithelial mononuclear cells were TGF-beta1-. Keratinocytes in OLP stained weakly for TGF-beta1. Unstimulated OLP lesional T cells secreted IFN-gamma in vitro. TNF-alpha stimulation down-regulated IFN-gamma secretion and up-regulated TNF-alpha secretion. IL-4, IL-10 and TGF-beta1 secretion were not detected.. These data suggest the development of a T helper 1 immune response that may promote CD8+ cytotoxic T-cell activity in OLP.

Topics: Adolescent; Aged; CD8-Positive T-Lymphocytes; Cell Count; Cells, Cultured; Cytokines; Humans; Immunohistochemistry; Interferon-gamma; Keratinocytes; Lichen Planus, Oral; Male; Middle Aged; Receptors, Immunologic; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th1 Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The basal cells in epithelium of the erythematous form of oral lichen display hyperproliferation compared with normal oral mucosa. In this study we examined whether this is associated with disrupted production, activation, or signal transduction of the epithelial growth inhibitor transforming growth factor (TGF) beta1. In situ immunostaining showed that most epithelial cells in normal oral mucosa had nuclear and cytoplasmic Smad4 and phosphorylated Smad2/3, but expressed little or no Smad7. Expression of latency-associated peptide TGF-beta1, latent TGF-beta binding protein 1, TGF-beta type I receptor, and TGF-beta type II receptor was readily seen, but only very little TGF-beta1 was activated. In erythematous oral lichen, basal and lower spinous epithelial layers showed staining for latency-associated peptide TGF-beta1, TGF-beta type I receptor, and TGF-beta type II receptor. A band with scanty staining for these molecules, but with marked staining for active TGF-beta1, was seen in the upper spinous and granular layers. Numbers of epithelial cell nuclei with Smad4 and phosphorylated Smad2/3 staining were significantly reduced in erythematous oral lichen compared with normal oral mucosa. Basal and suprabasal cell layers in erythematous oral lichen showed strong cytoplasmic Smad7 protein staining, but in spinous and granular layers Smad7 was localized to the cell membrane. In situ hybridization showed strong Smad7 mRNA expression in almost all basal keratinocytes in erythematous oral lichen; by contrast, no or occasionally very weak Smad7 mRNA expression was seen in these cells in normal oral mucosa. The observations indicate that inhibition of the TGF-beta/Smad pathway may account for the hyperproliferation of keratinocytes in erythematous oral lichen.

Topics: Cell Division; Cell Nucleus; DNA-Binding Proteins; Epithelial Cells; Gene Expression; Humans; Lichen Planus, Oral; Mouth Mucosa; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Smad7 Protein; Trans-Activators; Transforming Growth Factor beta

The symposium on Virus Infections and Tumors of the Oral Mucosae was organized as a joint meeting of the Arbeitskreis Oralpathologie and Oralmedizin and the Arbeitsgemeinschaft Dermatologische Infektiologie (ADI) der Deutschen Dermatologischen Gesellschaft. The main topics of the meeting were herpes virus infections, human papillomavirus (HPV) infections and human immunodeficiency virus (HIV) infections of the oral mucosae. Clinically both diagnostic, differential diagnostic and therapeutic aspects of the virus-associated diseases were discussed in several presentations. Another important issue was the role of these viruses, particularly of HPVs, in the origin and development of oral cancer. Apparently besides smoking and alcohol other risk factors comprise high risk HPVs, immunodeficiency and possibly also genetic factors. Whether neonatal early infections may predispose children to a specific cancer risk in their future life is still at a level of discussion. Some arguments, however were shown that tonsillar carcinoma, which shows the highest prevalence of the high-risk HPV 16- DNA sequences between all oral cancer, is possibly an epidemiologically and etiologically distinct tumor. It is argued that this tumor is probably less dependent on classical carcinogens than other oral malignant tumors.

Topics: DNA, Viral; Genes, p53; Herpesviridae Infections; HIV Infections; Humans; Leukoplakia, Oral; Lichen Planus, Oral; Mouth Neoplasms; Papilloma; Papillomaviridae; Papillomavirus Infections; Transforming Growth Factor beta; Tumor Virus Infections

In the present study, MRNA for the cytokines interleukin-2 (IL-2), IL-4, IL-10 tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor beta-1 (TGF-beta-1) were investigated in oral lichen planus (OLP) lesions using in situ hybridization with 35S-labelled oligonucleotide probes on frozen tissue sections. In addition, the expression of interferon-gamma (IFN-gamma), IL-10 and IL-4 mRNAs was analysed in cultured lesional T lymphocytes from oral lichen planus by polymerase chain reaction. Cells expressing mRNA for IL-2, IL-4, IL-10, TNF-alpha and TGF-beta 1 were found in all the biopsies studied. Approximately 1-2% of the total number of infiltrating cells in the lesions were positive for each of the different cytokine mRNAs. Most biopsies contained basement membrane-oriented, mRNA-positive cells. In the cultured T-cell lines, message for IFN-gamma was detected in all the patients, IL-10 in all but one, and IL-4 in just one of the seven patients investigated. The results suggest that mRNA for both pro- and anti-inflammatory cytokines, i.e., mixed T-helper 1 (TH1) and TH2 cytokine profiles, are generated simultaneously by a limited number of cells in chronic lesions of OLP.

Topics: Adult; Aged; Aged, 80 and over; Cells, Cultured; Female; Humans; In Situ Hybridization; Interleukin-10; Interleukin-2; Interleukin-4; Lichen Planus, Oral; Male; Middle Aged; Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To explore significance of transforming growth factor beta 1 (TGF beta 1) in the pathogenesis of oral submucous fibrosis (OSF), TGF beta 1 mRNAs in keratinocytes of the paraffin embeded tissues of 25 OSF cases, 5 normals (NOR) and 10 oral lichen planus (OLP) were determined by the in situ hybridization technique. The result showed that there was an expression of TGF beta 1 mRNA in keratinocytes of 15 OSFs (60%). The positive expression of TGF beta 1 mRNA was mainly in kerationcytes of early and middle stage OSF. There was no expression in that of 5 NORs and 10 OLPs. The study suggests that keratinocytes of OSF tissue may synthesize and release TGF beta 1 which may play an important role in the pathogenesis of OSF and participate as a mediator in the pathogenetic process of OSF.

Topics: Humans; Keratinocytes; Lichen Planus, Oral; Oral Submucous Fibrosis; RNA, Messenger; Transforming Growth Factor beta