interleukin-8 and Stomatitis--Aphthous

We reported a case of a 22-year old female with a microscopic form of polyarteritis nodosa (PN) who initially manifested Behçet's disease-like symptoms, such as fever, arthralgia, oral aphtha and erythema nodosum, and rapidly progressive glomerulonephritis (RPGN). On admission, her urinalysis showed active nephritic syndrome and her renal function rapidly deteriorated; serum creatinine levels elevated from 1.2 to 3.9 mg/dl within 2 weeks. Skin biopsy specimens from erythema showed panniculitis. Accordingly, she was treated with daily 30 mg of oral prednisolone and three-day intravenous pulse therapy of 1000 mg of methylprednisolone twice. After treatment, skin eruption and oral aphtha disappeared, and the serum creatinine level improved to 1.2 mg/dl. Percutaneous renal biopsy performed on the 28th day showed focal necrotizing glomerulonephritis and hyalinosis of small arteries. Immunofluorescence studies showed only trace stainings for IgG, IgA and beta lc. Electron microscopic findings revealed fusion of the foot process and swelling of endothelial cells, but no dense deposits. Anti-neutrophil cytoplasmic antibody (ANCA) was positive for IgG class with a 40-fold titer by indirect immunofluorescence test and showed a cytoplasmic pattern combined with high urinary IL-8 level (280.1 pg/ml). We diagnosed this case as a microscopic form of PN. ANCA titer and urinary IL-8 correlated positively with the disease activity, and were finally below 8-fold and 58.6 pg/ml, respectively after resolution of RPGN for 42 months. In this case, ANCA was useful not only for differential diagnosis of the patients with systemic vasculitis and crescentic glomerulonephritis, but also for evaluation of the disease activity.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Behcet Syndrome; Disease Progression; Erythema Nodosum; Female; Glomerulonephritis; Humans; Interleukin-8; Polyarteritis Nodosa; Stomatitis, Aphthous

Azelastine (azelastine hydrochloride) was orally administered to 43 patients with recurrent aphthous ulcers (RAU), and its clinical effects and in vitro influence on leukocytes were examined. During at least 6 months after drug treatment, no oral ulcers occurred in 7 patients, and an improvement of the oral condition was exhibited in all except 4 of the remaining patients. The frequency of occurrence of RAU was significantly reduced, from 1.7 +/- 0.9 to 0.9 +/- 0.5 times/month, and ulcer duration and oral irritation were also significantly reduced from 12.5 +/- 2.5 and 7.5 +/- 2.4 days to 9.8 +/- 2.6 and 5.3 +/- 2.4 days, respectively. Neutrophils from patients treated with Azelastine generated a suppressed volume of superoxide (O2-). Suppression of O2- generation and chemiluminescence by in vitro Azelastine was also confirmed to occur in a dose-dependent manner. Furthermore, the production of TNF-alpha and GM-CSF in lymphocytes was suppressed in the presence of Azelastine, and the drug protected sheep red blood cells and epithelial tumor cell lines against hydrogen peroxide impairment and hypotonic shock. These clinical and experimental results lead to the conclusion that improvement of RAU by Azelastine depends on the protection of cell membranes and the suppression of leukocyte-function, including reactive oxygen generation.

Topics: Adolescent; Adult; Aged; Cell Survival; Child; Erythrocytes; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Lipoxygenase Inhibitors; Luminescent Measurements; Male; Middle Aged; Neutrophils; Oxides; Phthalazines; Recurrence; Stomatitis, Aphthous; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

A recurrent aphthous ulcer (RAU) is a common inflammatory ulcerative lesion affecting oral mucosa. We studied the eventual apoptosis of epithelial cells from the point of view of ulcer and inflammation. RAU lesions and healthy mucosa samples were immunostained for caspase-3 and high-mobility group box 1 (HMGB1). DNA nicks were identified using TUNEL staining. We studied the effects of tumor necrosis factor α (TNFα) and interferon γ (IFNγ) on the toll-like receptor 2 and 4 (TLR2 and TLR4) expression of human oral SCC-25 keratinocytes. We also studied the effects of self-DNA, all-thiol-HMGB1, and disulfide-HMGB1 on epithelial cells, with or without IFNγ. At the edge of RAU lesions, all epithelial cell layers were caspase-3(+), TUNEL(+), and HMGB-1(+) and had widened intercellular spaces. In contrast, healthy epithelial cells were negative for caspase-3 and TUNEL staining. HMGB1 was seen in only the basal cell layers, and the cells retained close cell-to-cell contacts. Self-DNA increased TNF-α mRNA (P = 0.02) in SCC-25 cells. Both TNFα and IFNγ (P = 0.01) increased TLR2. Upon TNFα stimulation, SCC-25 cells lost their nuclear HMGB1 staining. HMGB1 did not increase IL-8, IL-6, or TNF-α mRNA in SCC-25 cells, which was unaffected by the presence of IFNγ. We conclude that in healthy epithelium, the most superficial cells at the end of their life cycle are simply desquamated. In contrast, RAU is characterized by top-to-bottom apoptosis such that dead cells may slough off, leading to an ulcer. Because of a lack of scavenging anti-inflammatory macrophages, apoptotic cells probably undergo secondary necrosis releasing proinflammatory danger signals, which may contribute to the peripheral inflammatory halo. This is supported by self-DNA-induced TNFα synthesis. In contrast to TLR4- and TLR2-binding lipopolysaccharide used as a positive control, disulfide-HMGB1 did not stimulate proinflammatory cytokines.

Topics: Adult; Aged; Apoptosis; Caspase 3; Cell Culture Techniques; Cell Line; Cell Nucleus; Epithelial Cells; Extracellular Space; HMGB1 Protein; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation Mediators; Interferon-gamma; Interleukin-6; Interleukin-8; Keratinocytes; Middle Aged; Mouth Mucosa; Stomatitis, Aphthous; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Young Adult

Recurrent aphthous ulcer (RAU) is an ulcerative disease of non-keratinized oral mucosa. Colon and bronchial epithelial cells produce interleukin-17C (IL-17C) upon stimulation of Toll-like receptor 2 (TLR2), TLR3 and TLR5, which are highly expressed in epithelial cells in RAU lesions. We therefore investigated the eventual presence and function of IL-17C in cultured human oral keratinocytes (HOK) and control biopsies compared to RAU lesions.. Expression of IL-17A, IL-17C, IL-17RA and IL-17RE was analysed in cultured HOK cells using quantitative real-time polymerase chain reaction (qRT-PCR). HOK cells were stimulated with IL-17C and analysed for IL-8 and tumour necrosis factor-α (TNF-α) using qRT-PCR. Control mucosa (n = 5) was immunostained for IL-17A, IL-17C, IL-8, TNF-α and mast cell tryptase and compared with RAU lesions (n = 5) using the mean grey scale value.. IL-17C, but no IL-17A, mRNA was found in cultured HOK cells. Components of the heterodimeric IL-17RA/IL-17RE receptor for IL-17C were also highly expressed. Stimulation of HOK with IL-17C increased TNF-α mRNA (P = 0.03; IL-8 increase was not statistically significant). HOK in RAU lesions stained intensively for IL-17C compared to controls (P = 0.006). This was associated with increased epithelial immunostaining of TNF-α (P = 0.04) and IL-8 (P = 0.02). Most of the inflammatory cells which stained for IL-17A in control mucosa and RAU lesions were also mast cell tryptase positive.. IL-17C is highly expressed in epithelial cells in RAU lesions, where it seems to stimulate oral keratinocytes via IL-17RA/IL-17RE to produce pro-inflammatory cytokines. Human oral epithelial cells are probably important inflammatory cells in RAU.

Topics: Adolescent; Adult; Aged; Biopsy; Cell Culture Techniques; Cells, Cultured; Child; Epithelial Cells; Fluorescent Antibody Technique; Humans; Interleukin-17; Interleukin-8; Keratinocytes; Middle Aged; Mouth Mucosa; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-17; Stomatitis, Aphthous; Tryptases; Tumor Necrosis Factor-alpha; Young Adult

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature.. 23 children with PFAPA (age 6.07 ± 2.94 years, range 5-9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1-17 years) participated in the study. Peripheral blood concentrations of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology.. PFAPA febrile episodes were characterized by detection of GM-CSF - 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1β was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects.. PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.

Topics: Adolescent; Child; Child, Preschool; Cytokines; Female; Fever; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant; Interleukin-8; Male; Pharyngitis; Stomatitis, Aphthous; Syndrome

Recurrent aphthous ulcerations (RAU) are common oral inflammatory lesions. Interleukin (IL)-8 is a pro-inflammatory cytokine of host response to injury and inflammation. Our recent study has found that measurement of serum IL-6 level can detect only 24% RAU patients with an abnormal serum level. In this study, we examined both the serum IL-6 and IL-8 levels in a group of RAU patients. The abilities of IL-6 and IL-8 to detect patients with an abnormal serum level were compared in order to find out whether IL-8 was a more sensitive serum marker than IL-6 in monitoring the disease activity of RAU.. In this study, we used a solid-phase, two-site sequential chemiluminescent immunometric assay to determine the baseline serum levels of IL-6 and IL-8 in 146 patients with RAU, 9 patients with traumatic ulcers (TU), and 54 normal control (NC) subjects. Eighty-two RAU patients, with the serum IL-6 or IL-8 levels higher than the upper limit of normal serum concentration, were treated with levamisole for 0.5-3.5 months, and their serum IL-6 and IL-8 levels were measured after treatment.. We found that 25% (37/146) RAU patients, as well as 33% (20/61) major-type, 19% (13/69) minor-type, and 25% (4/16) herpetiform-type RAU patients, had a serum level of IL-6 greater than the upper normal limit of 4.7 pg/ml. In contrast, 60% (87/146) RAU patients, as well as 59% (36/61) major-type, 59% (41/69) minor-type, and 63% (10/16) herpetiform-type RAU patients, had a serum level of IL-8 greater than the upper normal limit of 8.7 pg/ml. In 82 RAU patients with the serum IL-6 or IL-8 levels higher than the upper limit of normal serum concentration, treatment with levamisole for a period of 0.5-3.5 months could significantly reduce the serum IL-6 level from 12.0 +/- 1.6 to 3.0 +/- 0.5 pg/ml (P < 0.001), and could significantly lower the serum IL-8 level from 70.9 +/- 11.2 to 13.8 +/- 3.1 pg/ml (P < 0.001).. Because measurement of serum IL-8 level can detect 60% RAU patients with an abnormal serum level, while measurement of serum IL-6 level can detect only 25% RAU patients with an abnormal serum level, we conclude that serum IL-8 level is a more sensitive marker than serum IL-6 level in monitoring the disease activity of RAU. Levamisole can modulate both the serum IL-6 and IL-8 levels in RAU patients. IL-8, like IL-6, is also a useful serum marker in evaluating therapeutic effects of levamisole on RAU patients.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antirheumatic Agents; Biomarkers; Case-Control Studies; Child; Female; Humans; Interleukin-6; Interleukin-8; Levamisole; Male; Middle Aged; Sensitivity and Specificity; Stomatitis, Aphthous