Serum concentration of IL-17, IL-23 and TNF-α among patients with chronic spontaneous urticaria: association with disease activity and autologous serum skin test.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disorder, which is considered in a subset of patients to be an autoimmune disorder. T helper 17 (Th17) cells are crucially involved in the pathogenesis of some autoimmune diseases. OBJECTIVES: Our aim was to test the association of Th17 with CSU. We examined interleukin (IL)-17, IL-23 and tumor necrosis factor-alpha (TNF-α) serum levels in CSU patients and studied their association with urticaria activity and autologous serum skin test (ASST). SUBJECTS AND METHODS: Serum concentration of IL-17, IL-23 and TNF-α were measured in 75 patients with CSU and 30 healthy control subjects. Disease activity was assessed by using urticaria activity score (UAS) as recommended by EAACI/GA(2)LEN/EDF/WAO Guidelines. RESULTS: Serum concentration of IL-17, IL-23 and TNF-α were significantly higher in CSU patients as compared with the healthy control subjects (mean: 35.51 ± 31.14 vs. 4.60 ± 1.38 pg/mL; P < 0.001, 38.95 ± 27.82 vs. 9.87 ± 4.62 pg/mL; P > 0.001 and 17.93 ± 6.05 vs. 6.87 ± 3.73 pg/mL; P = 0.004, respectively). There were significant positive correlation between serum IL-17, IL-23, TNF-α and disease activity assessed by cumulative UAS for 7 days before blood sampling. The Serum concentration of IL-17, IL-23 and TNF-α were also significantly higher in ASST positive patients than in ASST negative patients. CONCLUSION: Our results showed high serum levels of IL-17, IL-23 and TNF-α among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of this important and common skin disease. It also may provide the rationale for new treatment strategies in chronic urticaria.

Benign prostatic hyperplasia. The Saudi perspective in the year 2000.

All published data on benign prostatic hyperplasia in Saudi Arabia was reviewed. The age of presentation of the benign prostatic hyperplasia Saudi patient is between 60 and 70 years. Until the introduction of medical therapy for benign prostatic hyperplasia, presentation by complication was common, mainly by retention of urine in 40-50% of the cases. Diagnostic modalities are improving and both biochemical and imaging techniques are now available. Medical therapy for benign prostatic hyperplasia is widely used but studies on only 2 alpha adrenergic blocking agents out the 5 pharmacological preparations currently in the field were reported. Those are Prazosin and Terazosin. Several studies on the use of the 5-alpha reductase enzyme inhibitor Finastride were also reported. Minimally invasive surgery, other recent techniques including laser technology and standard surgical techniques such as open prostatectomy and Trans-urethral Resection of the Prostate are reported to be efficiently utilized. The workload due to benign prostatic hyperplasia is increasing and estimated currently to be 20-40% of the whole urological workload. Late and complicated presentations still pose a serious medical problem. Screening programs and enhancement of awareness are required to ensure early presentation. The diagnostic modalities have improved and need to further improve by making both PSA testing and ultrasonography as standard procedures. Most advanced methods of medical and surgical treatment are available. More studies researching all aspects of benign prostatic hyperplasia are needed to improve patient care.

Evidence for the involvement of protein kinase C isoforms in alpha-1 adrenergic activation of phospholipase A2 in FRTL-5 thyroid cells.

BACKGROUND: FRTL-5 thyroid cells are a cell line extensively used for the investigation of thyroid functions. Activation of alpha-1 adrenergic receptors stimulates both arachidonic acid (AA) release and cytosolic Ca2+ increase in this cell line. Cytosolic Ca2+ and arachidonic acid are known to be important second messengers regulating a variety of thyroid functions. The generation of these messengers is regulated primarily by two different types of phospholipases, phospholipase C (PLC) and phospholipase A2 (PLA2). METHODS: Norepinephrine (NE, 10 mumol/L) was used as an alpha-1 adrenergic activator, and cytosolic-free Ca2+ concentration ([Ca2+]i) was determined using the fluorescent dye indo-1. Arachidonic acid release was measured as an indicator of PLA2 activation, and protein kinase C (PKC) activity determination and isoforms identification were performed using commercial kits. RESULTS: Norepinephrine increased [Ca2+]i and AA release. Prevention of NE-induced cytosolic Ca2+ influx, either by removal of extracellular Ca2+ or by use of Ca2+ channel blockers, NiCl2 or CoCl2, inhibited AA generation entirely. Inhibition of NE-induced increase in [Ca2+]i by the Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), also significantly suppressed NE-induced AA release. Inhibition of PKC activity by PKC inhibitors (H-7 or staurosporine) or downregulation induced by prolonged treatment with phorbol 12-myristate 13-acetate (PMA) or thyleametoxin (TX) significantly blocked the NE-induced AA release, which indicates PKC is involved in mediating NE-induced AA release. Protein kinase C activity measurement indicated that NE induced an activation of PKC in 5 minutes. To further characterize the role of PKC or Ca2+ in regulation of AA release, we identified PKC isoforms by immunoblotting with specific antibodies against 8 different Protein kinase C isoforms. PKC-alpha, -beta I, -beta II, -gamma, delta, -epsilon, -zeta, and -eta isoforms were identified. Norepinephrine induced translocation of PKC-alpha, -beta I, -beta II, -gamma, -delta, and -epsilon isoforms but not -zeta and -eta from cytosol to membrane. Chelation of intracellular Ca2+, prevention of Ca2+ influx, or prolonged treatment with thymeleatoxin (TX) completely blocked the NE-induced translocation of PKC-alpha. CONCLUSIONS: These results, taken together with data obtained from AA experiments, suggest that PKC plays a critical role in alpha-1 adrenergic receptor mediated PLA2 activation and subsequent AA release. Extracellular Ca2+ influx is a prerequisite for both PKC-alpha translocation and AA release. Whether Ca2+ acts directly upon the PLA2, or via PKC-alpha, to regulate AA generation is an intriguing question that remains to be clarified.

Immunoglobulins from Graves' disease patients stimulate phospholipase A2 and C systems in FRTL-5 and human thyroid cells.

We have studied the effects of immunoglobulin G from Graves' disease patients on phospholipase A2 (PLA2) and C(PLC) systems in FRTL-5 and human thyroid cells. Immunoglobulin G (IgG) from Graves' disease patients stimulated arachidonic acid (AA) release in a time- and dose-dependent manner. In FRTL-5 thyroid cells, removal of external calcium had no significant effect on the IgG (20 micrograms/ml)-induced AA release in FRTL-5 thyroid cells. U-73122 (3 mumol/l), a PLC inhibitor, and quinacrine (100 mumol/l) but not U-26384 (5 mumol/l), PLA2 inhibitors, blocked the IgG-induced (20 micrograms/ml) AA release in FRTL-5 thyroid cells. Immunoglobulin G (100 micrograms/ml) also stimulated accumulation of inositol-1,4,5-triphosphate (IP3) in a time- and dose-dependent (20-300 micrograms/ml) manner in FRTL-5 cells. Immunoglobulin G from Graves' disease patients induced a significant increase of IP3 production (p = 0.01) compared to IgG from normal subjects. Removal of external calcium had no significant effect on the IgG-induced IP3 production. The PLC inhibitor U-73122 completely blocked IgG-induced IP3 production from FRTL-5 thyroid cells. Also, in human thyroid cells, IgG from Graves' disease patients induced a significant increase of AA release (p = 0.001) and IP3 production (p = 0.004) compared to the IgG from normal subjects. These data indicate that IgG from Graves' disease patients induced PLA2 activity that was PLC dependent, a pattern referred to as sequential activation. Our studies suggest that IgG from Graves' disease patients activates PLA2 and PLC systems in FRTL-5 and human thyroid cells. These signal transduction pathways could be involved in the pathogenesis of Graves' disease and future studies are warranted to investigate this area.

The influence of triiodothyronine, thyroxine, thyrotropin, and methimazole on thyroid cell MHC class II antigen expression.

We have studied the influence of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), and methimazole (MMI) on the expression of major histocompatibility (MHC) Class II antigen expression in human thyroid cells. T3, T4, TSH, and MMI in various combinations were added together with interferon-gamma (IFN-gamma) to human thyrocytes or to cultured FRTL-5 cells. Neither T3 nor T4, alone, caused inhibition of the IFN-gamma stimulation of thyrocyte HLA-DR expression. Moreover, the combination of both drugs at various concentrations did not inhibit this expression except only in low ranges (T3 at 0.3 nmol/liter and T4 at 12.9 nmol/liter). MMI only at a concentration of 3.0 mmol/liter caused significant inhibition of IFN-gamma-induced HLA-DR expression. However, the addition of T3 (range, 0.3-9.2 nmol/liter) or T4 (12.9-129.0 nmol/liter) prevented the MMI-induced inhibition. This phenomenon may be explained by the action of MMI on inhibiting the synthesis of T3 and T4. At a concentration of 100 microU/ml, TSH enhanced IFN-gamma-induced HLA-DR expression. It is possible that TSH induced the expression of large numbers of IFN-gamma receptors, thereby enhancing the production of HLA-DR in response to IFN-gamma. Our studies suggest that MMI does not alter thyrocyte HLA-DR expression in vitro, especially when combined with T3 or T4; however, MMI may still induce or perpetuate immune effects in vivo secondary to its influence on thyroid hormone production or thyroid antigen presentation.