Upregulation of epidermal growth factor receptor 4 in oral leukoplakia.

In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.

Up-regulation of EGF receptor and its ligands, AREG, EREG, and HB-EGF in oral lichen planus.

OBJECTIVE: This study aimed to investigate the roles of the epidermal growth factor receptor (EGFR) family members and their ligands in oral lichen planus (OLP). STUDY DESIGN: The expressions of 4 EGFR-like receptors and 6 EGF-like ligands were measured in OLP tissues from 10 patients and compared with the levels in normal oral mucosa (NOM) from 10 healthy donors. RESULTS: Of the receptors, only EGFR mRNA and protein were more highly expressed in OLP compared with NOM tissues. Regarding the ligands, the mRNAs of amphiregulin (AREG), epiregulin (EREG), and heparin-binding EGF-like growth factor (HB-EGF) were more highly expressed in OLP compared with NOM tissues. These ligands were strongly expressed by infiltrating lamina propria lymphocytes as well as epithelial keratinocytes in OLP lesions, as shown by immunohistochemistry. CONCLUSIONS: The enhanced EGFR expression on the keratinocytes in OLP lesions and the up-regulation of EGF-like ligands in keratinocytes and infiltrating mononuclear cells could contribute to the carcinogenesis and pathogenesis of OLP.

Evidence for the changes of antitumor immune response during lymph node metastasis in head and neck squamous cell carcinoma.

OBJECTIVE: This study aimed to elucidate the differences in antitumor immune responses between primary tumors and metastatic regional lymph nodes in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: The clonality of tumor-infiltrating lymphocytes in tissue specimens from 17 HNSCC patients was examined regarding their T-cell receptor (TCR) repertoires and their complementary determining region 3 (CDR3) size spectratyping. Cytokine expression profiles and T-cell phenotypes also were measured by using real-time quantitative polymerase chain reaction. RESULTS: The host immune responses to HNSCC cells, reflected by the TCR repertoire, differed between primary tumors and metastatic lymph nodes. CD8+-T cells and T helper type 1 (TH1)/T cytotoxic 1 (TC1) cell cytokine production in metastatic and nonmetastatic lymph nodes were similar. CONCLUSIONS: The antitumor immune response to HNSCC cells changes during lymph node metastasis, and HNSCC cells can escape the cytotoxic immune responses mediated by CD8+-T cells and TH1/TC1 cells. These results suggest that lymph node metastasis might be associated with changes in the nature of the primary tumor antigens.

The levels of vascular endothelial growth factor in the synovial fluid correlated with the severity of arthroscopically observed synovitis and clinical outcome after temporomandibular joint irrigation in patients with chronic closed lock.

OBJECTIVE: This study aimed to investigate the level of vascular endothelial growth factor (VEGF) in the temporomandibular joint (TMJ) synovial fluid (SF) and the severity of arthroscopically observed synovitis before and after visually guided TMJ irrigation (VGIR) in patients with chronic closed lock (CCL). In addition, the findings were correlated with the clinical outcome. STUDY DESIGN: Twenty-four patients with unilateral CCL, who underwent a second VGIR either as a repeated therapeutic TMJ irrigation or as a follow-up arthroscopy, were enrolled in the study. They were divided into either successful (s-group; n = 11) and unsuccessful (u-group; n = 13) groups. The VEGF level in the aspirated SF and the severity of synovitis were compared between the s- and u-groups. In each group, the same parameters were compared before and after VGIR. The correlation of the VEGF level with the severity of synovitis was also studied. RESULTS: At the first VGIR, the VEGF levels showed no significant differences when comparing s- and u-groups. At the second VGIR, the VEGF level was significantly higher in the u-group. The VEGF level significantly decreased after the first VGIR in the s-group but remained unchanged in the u-group. There was no significant correlation between the VEGF level and the severity of synovitis. CONCLUSIONS: The level of VEGF in TMJ SF seems to reflect the clinical status in patients with CCL. Moreover, VEGF may be an important target molecule in future chemotherapy of TMJ CCL.

Inhibition of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 reduces the severity of collagen-induced arthritis.

OBJECTIVE: To investigate whether the blockade of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) has any therapeutic effects on rheumatoid arthritis. METHODS: A functional blocking monoclonal antibody for SHPS-1 (anti-SHPS-1 mAb) was administered at various doses to collagen-induced arthritis (CIA) mice, and severity of the arthritis was evaluated by clinical and histological scores of the limbs. To clarify the mechanisms of action of the antibody, the serum concentration of anti-type II collagen antibody was measured in those mice, and in vitro experiments were conducted to determine the effects of the antibody on the induction of osteoclasts and the release of cytokines from mouse spleen cells. RESULTS: Compared with mice given control IgG, the administration of anti-SHPS-1 mAb significantly reduced the severity of inflammation and destruction of bone and cartilage in CIA mice. This therapeutic effect was observed even when the antibody treatment was started after the onset of arthritis. The appearance of anti-type II collagen antibody in CIA mice was not altered by the antibody treatment. In in vitro experiments, the anti-SHPS-1 mAb significantly inhibited osteoclastogenesis of bone marrow cells, and significantly reduced the release of interleukin 1beta (IL-1beta), IL-2, IL-12, interferon-gamma, and tumor necrosis factor-alpha, but not that of IL-4 or IL-10, from the spleen cells after stimulation with concanavalin A. CONCLUSION: Administration of a monoclonal antibody for SHPS-1 reduced the severity of arthritis in CIA mice. Regulation of biological functions of SHPS-1 may be a novel and potent strategy to treat patients with rheumatoid arthritis.

Severity of arthroscopically observed pathology and levels of inflammatory cytokines in the synovial fluid before and after visually guided temporomandibular joint irrigation correlated with the clinical outcome in patients with chronic closed lock.

OBJECTIVE: This study aimed to investigate the severity of arthroscopically observed pathologies and the levels of a set of inflammatory cytokines in aspirated synovial fluid (A-SF) in patients with chronic closed lock (CCL) of the temporomandibular joint (TMJ) before and after visually guided TMJ irrigation (VGIR). Furthermore, the findings were correlated with the clinical outcome after VGIR. STUDY DESIGN: VGIR was performed in 56 consecutive patients with unilateral CCL. Forty-nine of them, who underwent a second VGIR either as a follow-up arthroscopy or as a repeated therapeutic irrigation, were analyzed. They were assigned to either the successful (s-) group (n = 31) or unsuccessful (u-) group (n = 18), according to the clinical success criteria. The severity of arthroscopic findings of osteoarthritis (OA), synovitis, and fibrous adhesion (FA) were evaluated as arthroscopic scores. The levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-12, and IL-10 in the A-SF were measured. At the first and second VGIR, the arthroscopic scores and the levels of each investigated cytokine were compared between the s- and u-groups. In each group, same parameters were compared between the first and second VGIR. RESULTS: At the first and second VGIR, there are no differences in the arthroscopic scores between the s- and u-groups. After the first VGIR, the severity of synovitis significantly improved, that of OA was unchanged, and that of FA became worse in the s- and u-groups. At the first VGIR, the levels of IL-6 and IL-8 were significantly higher in the u-group, and the IL-10 level was significantly higher in the s-group. At the second VGIR, however, there were no differences in the levels of each investigated cytokine between the s- and u-groups. The levels of each cytokine did not significantly change between the first and second VGIR, regardless of the clinical outcome. CONCLUSIONS: VGIR may contribute to the remission of synovitis in patients with TMJ CCL. However, the severity of arthroscopically observed pathologies and the levels of each investigated cytokine do not seem to be reflected by the clinical state. Moreover even if the intra-articular inflammation is asymptomatic, an exacerbation may not be ruled out even after a successful VGIR.