Dexamethasone regulates IL-1β and TNF-α-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells

We have investigated both constitutive- and cytokine-induced secretion of interleukin-8 (IL-8) and its regulation by dexamethasone and 17-estradiol in normal human bone marrow stromal (HBMS), osteoblast-like cells (hOB), and osteosarcoma MG-63 cells. Although HBMS cells secrete low levels of IL-8 constitutively, treatment with IL-1 and tumor necrosis factor- (TNF-) induced IL-8 secretion. Their effects were synergistic but IL-8 production was not affected by 17-estradiol. Human osteosarcoma MG-63 cells also secreted low levels of IL-8 constitutively; the production was induced by IL-1 and TNF- and was also not affected by 17-estradiol. The magnitude of the response to cytokine stimulation of IL-8 in MG-63 cells was much lower than that of HBMS and hOB cells, indicating differences in response in normal and osteoblastic osteosarcoma cells. Dexamethasone (10^-7 M) significantly inhibited IL-1 plus TNF- stimulated IL-8 production in HBMS, MG-63, and hOB cells. The accumulated results demonstrate that IL-8 is secreted by HBMS, MG-63, and hOB cells, suggesting that IL-8 may play a role in the regulation of bone cell function. These data also emphasize the importance of glucocorticoids in controlling cytokine secretion in HBMS, hOB, and MG-63 cells.     

Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy and immunotherapy has resulted in minimal remissions. Alternative forms of therapy are therefore being sought. The present study investigated the sensitivity of RCC cell lines to several toxins used alone and in combination with other agents. RCC lines were relatively sensitive to the direct cytotoxic effect of diphtheria toxin (DTX), Pseudomonas aeruginosa exotosin A (PEA) and ricin. Furthermore, DTX in combination with tumor necrosis factor- (TNF-) resulted in synergistic cytotoxic activity. The mechanism of synergy was examined. A possible mechanism of resistance to TNF- in tumor cells is the expression of TNF- mRNA or protein. R11 cells did not constitutively express mRNA for TNF-, however, treatment of R11 cells with TNF- induced the expression of TNF- mRNA. When DTX was used in combination with TNF-, the level of TNF- mRNA induced by TNF- was markedly reduced. These studies suggest that DTX in combination with TNF- can overcome the resistance of RCC lines and that the marked downregulation of TNF- mRNA by DTX may play a role in the enhanced cytotoxicity seen with the combination of DTX and TNF-. Furthermore, the combination treatment might also potentiate the antitumor host responses. The implications of these findings in clinical therapy are discussed.     

Natural human IgG inhibits the production of tumor necrosis factor-α and interleukin-1α through the Fc portion

The overproduction of cytokines such as the tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) may cause further deterioration in the already critical condition of patients with shock, sepsis, and acute inflammation. The effectiveness of infusion therapy of natural human IgG to such patients is suggested to depend partly upon the inhibition of the productivity of these cytokines. In this study, we investigated the modulation effects of IgG and its fragments on the production of TNF- and IL-1, on human peripheral blood mononuclear cells (PBMC). The production of TNF- and IL-1 was found to be dose-dependently inhibited by IgG when stimulated by lipopolysaccharide (LPS), phytohemagglutinin (PHA), concanavalin A (Con A), and interleukin-2 (IL-2). However, no inhibition was seen when stimulated by phorbormyristate acetate (PMA). The F(ab)₂ fragment showed enhancing effects on cytokine production by LPS, while the Fc fragment showed not as much inhibitory effect as whole intact IgG. IgG showed no direct cytotoxic effect on PBMC. These data suggest that natural human IgG inhibits TNF- and IL-1 production by PBMC through the Fc portion. The results of this study led us to conclude that whole intact IgG may be the best form of therapeutic delivery.     

The preventive effects of OK432 on endotoxin-induced liver injury: Liver protection by the modulation of hepatic macrophage function

The present study was conducted to clarify whether endotoxin-induced liver injury could be improved by modulating the function of hepatic macrophages using OK432, an immunostimulant derived from Streptococcus. OK432 elevated the capacity of hepatic macrophages to produce superoxide and tumor necrosis factor (TNF), and enhanced the mRNA expression of interleukin-1-, -, and TNF- in liver nonparenchymal cells (NPC). However, intravenous (iv) preadministration of OK432 reduced the mRNA expression of TNF- in liver NPC enhanced by the endotoxin injection, decreased the serum level of GOT and lactic dehydrogenase (LDH), and improved the survival rate of endotoxin-injected rats. Histological examination revealed a significant reduction in cell vacuolization and focal necrosis in the livers of the endotoxin-injected rats pretreated with OK432. These results indicate that hepatic macrophages play a crucial role in endotoxin-induced liver injury, and that TNF- is one of the factors most likely to be implicated in the development of endotoxin-induced liver injury. Thus, it is suggested that the administration of OK432 provides liver protection by modulating the responsiveness of hepatic macrophages against endotoxin.     

Cytotoxic effects of alpha- and gamma-interferon and tumor necrosis factor in human bladder tumor cell lines

We investigated the activity of alpha-interferon (-IFN), gamma-interferon (-IFN) and tumor necrosis factor-alpha (TNF-) in a panel of ten human bladder tumor cell lines. All cytokines were tested at concentrations of 100–10000 U/ml in a clonogenic assay system. We found that -IFN was active against five of the ten lines while -IFN was only active against one line. TNF was active against five of the ten lines. Maximum synergisms were obtained between the -IFN and TNF, occurring in nine of the ten cell lines. We conclude that -IFN and TNF are active as single agents and synergistic when used together in vitro in human bladder tumor cell lines.     

Estrogen Receptor Alpha in Human Breast Cancer: Occurrence and Significance

Estrogens have long been recognized as being important for stimulating the growth of a large proportion of breast cancers. Now it is recognized that estrogen action is mediated by two receptors, and the presence of estrogen receptor (ER)³ correlates with better prognosis and the likelihood of response to hormonal therapy. Over half of all breast cancers overexpress ER and around 70% of these respond to anti-estrogen (for example tamoxifen) therapy. In addition, the presence of elevated levels of ER in benign breast epithelium appears to indicate an increased risk of breast cancer, suggesting a role for ER in breast cancer initiation, as well as progression. However, a proportion of ER-positive tumors does not respond to endocrine therapy and the majority of those that do respond eventually become resistant. Most resistant tumors remain ER-positive and frequently respond to alternative endocrine treatment, indicative of a continued role for ER in breast cancer cell proliferation. The problem of resistance has resulted in the search for and the development of diverse hormonal therapies designed to inhibit ER action, while research on the mechanisms which underlie resistance has shed light on the cellular mechanisms, other than ligand binding, which control ER function.     

Bone Mineral Density of the Lumbar Spine is Associated with TNF Gene Polymorphisms in Early Postmenopausal Japanese Women

We investigated the relationships between tumor necrosis factor (TNF) gene polymorphism, circulating TNF-alpha (TNF-) concentrations, and bone mineral density (BMD) in the lumbar spine. TNF gene polymorphisms studied were the Nco I polymorphism within the first intron of TNF-beta (TNF-) and three single nucleotide polymorphisms in the promoter region of the TNF- gene, at positions –857, –863, and –1031. Allelic variants of the TNF gene were identified using restriction fragment length polymorphism (RFLP) analysis in 177 postmenopausal Japanese women within 10 years after menopause, aged 56.4 ± 4.5 years (mean ± SD). A significantly higher prevalence of the alleles TNF--863A (20.3% versus 9.9%) and TNF--1031C (21.3% versus 12.4%) was seen in the low BMD group (Z-score < 0, n = 91) than in the high BMD group (0 Z-score, n = 86). In genotype analysis, although difference did not reach a significant level, women with the rarest allelic variants, i.e., homozygous TNFb1, TNF--863A, and TNF--1031C, showed the lowest BMD Z-scores. Women with another rarest allelic variant, TNF--857T/T had significantly lower BMD Z-scores than did women with TNF--857C/T or –857C/C. The BMD Z-score decreased significantly with an increase in the total number of such rare alleles. Serum concentrations of TNF- did not differ significantly among groups divided by genotypes. Multiple linear regression analysis revealed that the total number of rare alleles, in addition to the body mass index and the number of years since menopause, was an independent predictor of the BMD. These presumptive functional polymorphisms of the TNF gene may be associated with the lumbar spine BMD in early postmenopausal Japanese women.     

Chronic intramedullary infusion of interleukin-1α increases bone mineral content in rats

Interleukin-1 (IL-1) is known to have a potent bone-resorbing activity in vitro, however, results from in vivo studies are conflicting. We performed experiments with the continuous infusion of recombinant IL-1 directly into the femoral bone marrow of rats for 2 weeks and examined its effects on bone by soft X-ray photographs, bone mineral assessment, and histological examination. Infusion of IL-1 at doses greater than 1 g/ml (0.6 ng/hour) caused sclerosis around the infusion site on soft X-ray photographs, and the bone mineral content of IL-1 infused femora was increased significantly. Histologically, extensive periosteal bone formation was observed around the infusion site and small mononuclear cells replaced the normal fat tissue. Infusion of prostaglandin E₂ alone produced intramedullary bone formation more extensively. Simultaneous infusion of IL-1 and indomethacin (10^-3 M; 179 ng/hour) inhibited the increase of bone mineral content (BMC) induced by IL-1. Thus, the chronic intramedullary administration of IL-1 stimulates bone formation, especially in the periosteum, and increases BMC in intact rats.     

Plasma proteins present in human cortical bone: Enrichment of theαHS-glycoprotein

The spectrum of plasma proteins present in human cortical bone and permanent dentine has been determined. One plasma glycoprotein, theHS-glycoprotein, was found to be present at a high concentration in both bone and dentine and was shown to be concentrated in the mineralized tissues with respect to the other plasma proteins by factors of between 30 and 100. In this respect theHS-glycoprotein is analogous to the G2B-glycoprotein and -glycoprotein of bovine and rabbit b one, respectively. The binding ofHS-glycoprotein and albumin to calcium phosphates generated within serum samples has been studied at different serum: precipitate ratios. In each case all theHS-glycoprotein was removed from the samples and theHS-glycoprotein was concentrated with respect to albumin by factors ranging from 370 at the highest serum: precipitate ratio to 25 at the lowest ratio. The plasmaHS-glycoprotein concentrations of patients with Paget's disease of bone were shown to be substantially lower than the normal range, with significant negative correlation between theHS-glycoprotein concentration and the plasma alkaline phosphatase activity.     

Impaired interferon-α production in whole-blood cultures from bladder cancer patients

Summary Interferon- (IFN-) production was investigated in whole-blood cultures of 66 bladder cancer patients and 65 control subjects. IFN synthesis was induced with Sendai virus, and IFN activity was assayed in FL cells challenged with vesicular stomatitis virus (VSV). The mean levels of the IFN- produced were 5,724±2,288 IU/ml in the control subjects and 4,800±2,353 IU/ml in the bladder cancer patients. IFN- production was significantly suppressed in the bladder cancer patients compared with that in the control subjects (P (0.05). The impairment in IFN- production correlated with the tumor grade, and it was shown that the tendency toward decreased IFN- production was closely associated with the advancement of the tumor stage. Our results suggested that the decreased IFN- production may contribute to the disordered immunoregulation in bladder cancer patients.     

Differentiation of pancreatic ductal carcinoma cells associated with selective expression of protein kinase C isoforms

Background: The signal transduction pathways important in regulating the growth and differentiation of malignant cells are poorly understood. Recent evidence has implicated activation of the protein kinase C (PKC) family of signaling proteins in pancreatic carcinoma during cytokine-induced cytostasis and differentiation. Methods: A human pancreatic adenocarcinoma (HPAC) cell line was exposed to tumor necrosis factor- (TNF-; 40 ng/ml) for 6 days. Cytostasis and viability were confirmed by daily MTT [(3(4,5)-dimethyl-thiazol-2-yl) 2,5-diphenyl-tetrazolium bromide] and trypan exclusion assay. Protein fractions were isolated daily and subjected to immunoblot analysis for the normal (terminally differentiated) pancreatic ductal cell marker carbonic anhydrase II (CA II) as well as specific PKC isoforms (, , , , and). Results: Growth arrest occurred in HPAC cells after exposure to TNF- for 48 h, with viability maintained above 90% throughout the 6-day time course. CA II immunoreactivity was not detected in untreated controls but appeared after 2 days of TNF- exposure, peaking on day 6. Concurrently, TNF- induced the selective downregulation of PKC-, whereas PKC- levels increased. PKC- and PKC- immunoreactivity did not change. The atypical PKC- isoform developed a doublet banding pattern in response to TNF-, although overall PKC- levels did not change. Conclusions: TNF--induced growth arrest and differentiation in HPAC cells is associated with the selective downregulation of PKC- and upregulation of PKC-.Presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Effects of pentoxifylline in Adriamycin-induced renal disease in rats

Tumor necrosis factor- (TNF-) is a mediator of inflammation in human and animal renal disease. Pentoxiphylline (PTX) is an inhibitor of TNF-. In this study we examined the effects of PTX on TNF-, proteinuria, nitrite production, and apoptosis in an experimental model of Adriamycin (ADR) nephropathy in rats. Rats were divided into four groups: untreated Wistar rats (controls), PTX treatment alone, ADR treatment alone to induce nephropathy, and ADR treatment followed by PTX. ADR treatment followed by PTX treatment prevented the increase in serum TNF- levels and proteinuria in rats with ADR-nephropathy (P<0.05). Urine nitrite levels were significantly increased in the ADR-induced nephropathy group and the increase was prevented in the ADR-induced nephropathy group when they also received PTX. The urine nitrite levels were not different between the PTX-treated group and the untreated control rats. PTX prevented the rise of serum TNF- in ADR nephropathy rats and a decrease in proteinuria, urine nitrite, and apoptosis in the renal tissue. These findings suggest a beneficial anti-inflammatory effect of PTX.     

In Vivo Effect of Tumor Necrosis Factor Alpha on Wound Angiogenesis and Epithelialization

Abstract Background: The role of tumor necrosis factor alpha (TNF-) in wound healing is unclear and the results are contradictory. In vivo, TNF- induces vessel growth, an important step in promoting wound healing. However, a reduced amount of collagen, hydroxyproline, and granulation tissue was found after TNF- treatment. It is also unknown if this is a direct effect, by influencing cells involved in wound healing, or an indirect effect due to a negative or positive effect on cells such as macrophages. Material and Methods: The current study was undertaken to test the effect of TNF- on wound epithelialization and neovascularization in vivo. In the first experiment, standardized full-thickness dermal wounds (2.25 mm diameter, 0.125 mm depth) were created on the dorsum of the ears of male hairless mice. The wounds were treated either with TNF- (100 ng/ml, 1 µg/ml, 5 µg/ml; n = 10 per group), monoclonal TNF- antibody (10 µg/ml; n = 10), or vehicle (n = 10). Wound epithelialization and neovascularization were analyzed every 3rd day by intravital microscopy until complete healing.In a second experiment, the same wound model was used, but in order to impair the healing process, macrophages were depleted. To reduce macrophages, two out of four groups (n = 10 per group) were pretreated with iota-carrageenan (MR groups), and the other two groups received only saline (N groups). One N group and one MR group were treated with TNF- (1 µg/ml). The other N group and MR group received vehicle only (carboxymethylcellulose). Using intravital microscopy and computerized planimetry, wound epithelialization and neovascularization were measured every 3rd day until complete healing. Immunohistochemistry was performed to detect TNF-, macrophages, fibronectin, and vitronectin receptors. Results: In the first experiment the wounds treated with 1 µg/ml healed significantly earlier than controls (13.9 ± 2 vs. 17.3 ± 2.8 days, respectively; p < 0.05). Epithelialization in the antibody group was significantly slower compared to controls (20.1 ± 2 days; p < 0.05). Neovascularization was significantly enhanced in the group treated with 1 µg/ml TNF- (p < 0.05). In the second experiment the wounds treated with TNF- were significantly earlier epithelialized (13.1 ± 0.6) and vascularized (16.0 ± 0.5) compared to controls (16.8 ± 0.4 vs. 17.6 ± 0.5; p < 0.05). Wound closure was significantly delayed in the MR group treated with vehicle only (20.4 ± 1) and equal to controls in the MR group treated with TNF- (16.8 ± 0.6). Conclusion: The results demonstrate the TNF- accelerates wound epithelialization and neovascularization in this in vivo model. TNF- is able to compensate for the negative effect of macrophage reduction and seems to have a direct effect on the wound-healing process.     

Effect of tumor necrosis factor-α and interferon-γ on the growth of human prostate cancer cell lines

Human recombinant tumor necrosis factor- (rTNF-, 10^-12–10^-8 M) inhibited the proliferation of androgen-dependent LNCaP cells by 32–56%. In contrast, proliferation of androgen-independent PC-3 and JCA-1 cells was only slightly inhibited, or not inhibited at all, respectively. Human recombinant interferon- (rIFN-, 500 U/ml) decreased proliferation of PC-3 and JCA-1 cells by 35% and 53%, respectively, but had no effect on LNCaP cells. Interestingly, the combination of rIFN- and TNF- had greater antiproliferative effects on JCA-1 cells than treatment with either cytokine alone. However, the antiproliferative effects of this combination were similar to those observed for PC-3 or LNCaP cells treated with rIFN- or TNF- alone, respectively. These data suggest that some forms of androgen-independent prostate cancer may benefit from a combination therapy of IFN- and TNF-, while the use of IFN- alone may be more efficacious in others.     

Receptor function studies in specimens from the proximal human urethra obtained by transurethral resection

Summary During transurethral resection (TUR) for prostatic hyperplasia, specimens were taken from the proximal urethra. Muscle strips thus obtained were mounted in an organ bath and muscle contraction was induced by adding increasing concentrations of noradrenaline (NA), methoxamine (₁-agonist) and clonidine (₂-agonist). NA and methoxamine induced a dose-dependent muscle contraction, but clonidine had no effect. The influence of prazosin (₁-antagonist) and yohimbine (₂-antagonist) on the NA-induced muscle contraction was also evaluated. Both antagonists had an inhibitory effect,which was much more potent with prazosin. The specimens taken during TUR were found to be suitable for in vitro receptor function studies. The -adrenergic receptor function in the proximal human urethra was found to be mainly of the -type.     

The reducing end of αGal oligosaccharides contributes to their efficiency in blocking natural antibodies of human and baboon sera

Synthetic galactosyl oligosaccharides were tested for their ability to inhibit the cytotoxic reaction of human and baboon natural antibodies on PK15 cells in culture. Methyl--Gal gave weak inhibition, Gal1-3Gal substantially inhibited the reaction (400 M), and Gal1-3Gal2-4GlcNAc was ten times more efficient (30 M). The modification from to anomeric configuration of the nonreducing end resulted in a complete loss of activity, while substitutions at the reducing end induced only a partial loss of activity. These observations suggest that natural anti-Gal antibodies recognize the epitope from its nonreducing end, but that substitutions at the reducing terminus can modify the antibody-binding capacity. Modified tri- and tetrasaccharides are better inhibitors than the disaccharide but not as good as Gal1-3Gal1-4GlcNAc. The reducing terminus therefore contributes some energy to the reaction, indicating that certain oligosaccharides will be of more potential clinical use than others.     

Intratumoral IL-12 and TNF-α–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor (TNF-), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.Methods: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon (IFN) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis.Results: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF- leading to increased infiltration by polymorphonuclear cells and CD8⁺ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN- production, was highest with IL-12 and TNF-. This treatment resulted in resistance to tumor rechallenge.Conclusions: A single intratumoral injection of IL-12 and TNF-–loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8⁺ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.     

Absence of Severe Systemic Toxicity After Leakage-Controlled Isolated Limb Perfusion With Tumor Necrosis Factor-α and Melphalan

Background: Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor- (TNF-) and melphalan, with or without interferon-, have been reported in several series. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation.Methods: Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF- (3–4 mg) and melphalan, with or without interferon-, were studied. Leakage rates and TNF- levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes.Results: Only two patients experienced leaks (2% and 13%) during ILP. For 18 patients without leakage, the mean peak systemic TNF- level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF- levels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consisted mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first day after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolving spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited significantly higher TNF- levels after ILP, compared with other patients.Conclusions: Systemic toxicity after ILP with TNF- is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.     

Role of p38 MAP kinase pathway in a toxin-induced model of hemolytic uremic syndrome

The role of proinflammatory cytokines in a rat model of toxin-induced hemolytic uremic syndrome (HUS) was studied. Male Sprague-Dawley rats underwent continuous saline infusion (6 ml/h) via a tail vein and received a bolus injection of saline (control), lipopolysaccharide (LPS, 10 g/100 g body weight), ricin (6.7 g/100 g body weight), or ricin with LPS (ricin+LPS). They were then observed for 8 h. Blood samples and kidney tissues were obtained at the end of the experiment. The effects of FR 167653, a potent inhibitor of interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) production, were also examined in ricin+LPS-treated rats. Only ricin+LPS-treated rats developed significant thrombocytopenia, hemolysis, and oliguric acute renal failure with extensive glomerular thrombotic microangiopathy, which was characterized by glomerular microthrombi and apoptosis of glomerular endothelial cells. Thrombotic microangiopathy was not detected in other organs, including the brain, liver, spleen, pancreas, lung, colon, and intestine. Significantly elevated levels of serum IL-1 and TNF- were detected only in ricin+LPS-treated rats. Treatment of ricin+LPS-treated rats with FR 167653 significantly reduced the serum levels of IL-1 and TNF-, accompanied by improvement of the oliguric renal failure and glomerular thrombotic microangiopathy. These findings indicate that the increased serum levels of IL-1 and TNF-, which probably result in the apoptosis of glomerular endothelial cells, play a pivotal role in the development of this rat model of toxin-induced HUS. The findings also suggest that inhibition of these proinflammatory cytokines may prevent the development of HUS.     

The role of tumor necrosis factor-α in Henoch-Schönlein purpura

Henoch-Schönlein purpura (HSP) is one of the most common types of vasculitis disorders in childhood and is characterized by a rash, arthritis, abdominal pain, and renal involvement. The factors that determine and mediate the severity of HSP and its renal involvement remain poorly understood, although it is likely that pro-inflammatory cytokines, including tumor necrosis factor- (TNF-), are involved in the pathogenesis. Serum and urine levels of TNF- were measured in children with HSP in the acute and convalescent phases by ELISA. Serum TNF- levels were significantly higher in proteinuric HSP in the acute phase (36.6±8.5 pg/ml) compared with those with HSP without renal involvement and those with hematuric HSP (25.4±4.5 and 27.1±3.9 pg/ml) (P<0.005). However, these significantly higher levels disappeared in the convalescent phase. Using matched serum samples from the same patients, serum TNF- levels of proteinuric HSP patients were significantly lower in the convalescent phase (29.9±4.6 pg/ml, P <0.05) than in the acute phase (39.1±8.2 pg/ml). Although urine TNF- levels were higher in proteinuric HSP in the acute phase and reduced in the convalescent phase, there were no significantly high or low levels. These results suggest that increased TNF- levels in the serum induce a series of functional and morphological changes in the glomerular cells in the acute phase and may be used as markers for monitoring the disease activity of HSP with severe renal involvement.