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Macrophage Inflammatory Protein--1: A Prostaglandin-Independent Endogenous Pyrogen FEVER IS A HIGHLY COMPLEX REsponse in mammalian host defense that results in a temporary rise in basal temperature and appears to be [...]

Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disorder, which often involves referral to multiplemedical specialists. Lupus nephritis (LN) occurs in ∼35% of adults with SLE and predicts poor survival. There is currently no consensus on how to manage patients with SLE or LN across specialties and across different European countries. The Lupus Nephritis Terminology Advisory Group was formed to address this issue as it impacts upon LN treatment. It has developed consensus statements based on opinions from expert panel meetings with nephrologists, nephropathologists, rheumatologists, clinical immunologists and internal medicine specialists from many European countries, after reviewing current guidelines from the European League Against Rheumatism, the American College of Rheumatology and the participants' experience. In this article, we report consensus statements that were developed in six important areas: classification of patients with LN, how classification affects the selection of treatment options and definitions of induction, response, flare andmaintenance.We have also proposed a consensus for the terminology involved in the management of LN that is consistent with clinical opinion gathered from multidisciplinary expert meetings and with existing guidelines. We believe this consensus approach provides agreed expert opinion to clinicians and will form the basis for optimising LN treatment. [ABSTRACT FROM AUTHOR]

Unlabelled: Fever without localising signs in very young children remains a diagnostic problem. Until present, a clinical scoring system combined with leucocyte count, urine analysis and determination of CRP are recognised as being helpful to identify patients at risk of serious bacterial illness. In this study we asked the question whether the determination of procalcitonin (PCT), interleukin (IL)-6, IL-8 and interleukin-1 receptor antagonist (IL- Ra) was superior to these commonly used markers for the prediction of a serious bacterial infection (SBI). Children, 7 days to 36 months of age, with a rectal temperature above 38 degrees C and without localising signs of infection were prospectively enrolled. For each infant, we performed a physical examination, a clinical score according to McCarthy, a complete white cell count, an urine analysis and a determination of CRP. We further determined PCT, IL-6, IL-8, and IL-1Ra concentrations and compared their predictive value with those of the usual management of fever without localising signs. Each infant at risk of SBI had blood culture, urine and cerebrospinal fluid cultures when indicated, and received antibiotics until culture results were available. A total of 124 children were included of whom 28 (23%) had SBI. Concentrations of PCT, CRP and IL-6 were significantly higher in the group of children with SBI but IL-8 and IL-1Ra were comparable between both groups. PCT showed a sensitivity of 93% and a specificity of 78% for detection of SBI and CRP had a sensitivity of 89% and a specificity of 75%.Conclusion: Compared to commonly used screening methods such as the McCarthy score, leucocyte count and other inflammatory markers such as interleukin-6, interleukin-8 and interleukin- receptor antagonist, procalcitonin and C-reactive protein offer a better sensitivity and specificity in predicting serious bacterial infection in children with fever without localising signs. [ABSTRACT FROM AUTHOR]

Context: Studies have shown that an inflammatory response may be elicited by mechanical ventilation used for recruitment or derecruitment of collapsed lung units or to overdistend alveolar regions, and that a lung-protective strategy may reduce this response.Objective: To test the hypothesis that mechanical ventilation induces a pulmonary and systemic cytokine response that can be minimized by limiting recruitment or derecruitment and overdistention.Design and Setting: Randomized controlled trial in the intensive care units of 2 European hospitals from November 1995 to February 1998, with a 28-day follow-up.Patients: Forty-four patients (mean [SD] age, 50 [18] years) with acute respiratory distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.Interventions: After admission, volume-pressure curves were measured and bronchoalveolar lavage and blood samples were obtained. Patients were randomized to either the control group (n = 19): tidal volume to obtain normal values of arterial carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure (PEEP) producing the greatest improvement in arterial oxygen saturation without worsening hemodynamics; or the lung-protective strategy group (n = 18): tidal volume and PEEP based on the volume-pressure curve. Measurements were repeated 24 to 30 and 36 to 40 hours after randomization.Main Outcome Measures: Pulmonary and systemic concentrations of inflammatory mediators approximately 36 hours after randomization.Results: Physiological characteristics and cytokine concentrations were similar in both groups at randomization. There were significant differences (mean [SD]) between the control and lung-protective strategy groups in tidal volume (11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5] vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P<.001). Patients in the control group had an increase in bronchoalveolar lavage concentrations of interleukin (IL) 1beta, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage and plasma concentrations of tumor necrosis factor (TNF) alpha, IL-6, and TNF-alpha, receptors over 36 hours (P<.05 for all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar lavage concentrations of polymorphonuclear cells, TNF-alpha, IL-1beta, soluble TNF-alpha receptor 55, and IL-8, and in plasma and bronchoalveolar lavage concentrations of IL-6, soluble TNF-alpha receptor 75, and IL-1 receptor antagonist (P<.05). The concentration of the inflammatory mediators 36 hours after randomization was significantly lower in the lung-protective strategy group than in the control group (P<.05).Conclusions: Mechanical ventilation can induce a cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung. Whether these physiological improvements are associated with improvements in clinical end points should be determined in future studies. [ABSTRACT FROM AUTHOR]

We have studied the effect of systemic administration of etretin (Ro 10–1670) on the epidermal interleukin 1 (IL1) pool in the rat. Hairless rats were given varying doses of etretin intraperitoneally for 21 days, or a fixed dose for 2, 8 and 16 days. Abdominal skin was taken and processed for light microscopy, autoradiography (using [³H]-thymidine) and IL1 assays. IL1 was assayed in supernatants of epidermal extracts by both the lymphocyte activating factor (LAF) assay and the stimulation of prostaglandin E2 (PGE2) release from dermal fibroblasts. A significant increase in both LAF and PGE2 stimulatory activities was found during etretin administration. After 21 days' treatment with varying doses there was a two- to three-fold increase as compared to the controls, with a peak at 2 and 5 mg/kg. At a fixed dose a two-fold increase was found after 2 days and a three- to four-fold increase after 16 days; normal pretreatment values were restored 16 days after cessation of etretin. This is the first demonstration in vivo that a retinoid can modulate IL1 content in a tissue. As epidermal IL1 has been found to be decreased in psoriasis, its modulation by retinoids might have therapeutic significance. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis has occasionally been associated with congenital immunodeficiency. Recently, sclerosing cholangitis has been found in the course of AIDS and cryptosporidium or cytomegalovirus have been observed chronically in the biliary tract, suggesting their role in the evolution to sclerosing cholangitis. We report on 2 brothers with immunodeficiency without any evidence of AIDS, who showed sclerosing cholangitis and recurrent pulmonary infections in the course of their disease. No bacterial microorganism could be cultured from the biliary juice. The serum of both patients contained measurable levels of TNFα. Supernatants from cultured peripheral blood mononuclear cells of the two brothers contained higher amounts of tumor necrosis factor (TNFα), interleukins la and 1β than did supernatants from cultures of normal individuals. The role of cytokines as an aggravating factor in immunodeficiency is discussed as well as their role in the inflammatory process. [ABSTRACT FROM AUTHOR]

By means of direct cell-cell contact, fixed, stimulated T lymphocytes trigger the production of interleukin-1β (IL-1β) and turnout necrosis factor by monocytes and prime polymorphonuclear leucocytes (PMN) for the respiratory burst induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP). In order to assess whether this activity is displayed by a particular subpopulation of T lymphocytes, 88 T-cell clones (TCC) were generated from healthy human peripheral blood. The clones were stimulated by Phaseolus vulgaris agglutinin (PHA) and phorbol 12-myristate acetate (PMA), fixed with paraformaldehyde, and tested for their effect on PMN and the human monocytic cell line THP-1. All fixed, stimulated TCC induced IL-1β production by THP-1 cells, although to varied degrees. The activity of TCC on THP-1 cells correlated with their activity on PM N (r² = 0.84, P < 0.001), suggesting that this pro-inflammatory activity of TCC may similarly affect both types of infiltrating cells. The ability of TCC to modulate target cells did not correlate with either their phenotype (CD4 or CD8) or their cytokine production profile (interferon-γ IL-4 and IL-6), although it tended to correlate inversely with their capacity to produce IL-6 (P < 0.02). These observations suggest that a large proportion, if not all, of human peripheral blood T lymphocytes may potentially affect monocytes and PMN by direct cell-cell contact. This activity may be relevant to the maintenance of chronic inflammation. [ABSTRACT FROM AUTHOR]

Previous studies have shown that desferrioxamine (DFX), an iron chelator preventing the synthesis of hydroxyl radical (OH.), up-regulates the cell-surface expression of tumour necrosis factor-α (TNF-α) receptors on unactivated human blood monocytes. In the present study, we investigated the regulatory action of DFX on 125I-TNF-α binding to monocytes upon exposure to bacterial lipopolysaccharide (LPS). Exposure to LPS (1 µg/ml) resulted in almost complete loss of 125I-TNF-α binding to the surface of monocytes. This down-regulation was reversible and the recovery observed after 18 hr was enhanced by addition of DFX (5 mM). However, binding studies on monocytes preexposed to low pH suggested that the DFX-induced increase of 125I-TNF-α binding was not due to differences in the number of receptors available but was probably due to a reduction of receptor occupancy by endogenously generated TNF-α. Time-course studies of TNF-α release from monocytes confirmed the ability of DFX to reduce the extracellular concentration of bioactive TNFα through a decrease of its synthesis and an increase of its inactivation. The latter process was associated with an increased expression of the soluble form of TNF-α receptor type II. These results indicate that, in the presence of LPS, DFX increases the release of soluble TNF-α receptors from monocytes. Thus, conversely, OH. generated in situ could reduce the shedding of soluble TNF-α receptors and, hence, increase the widespread release of bioactive TNF-α. [ABSTRACT FROM AUTHOR]

The extracellular domain of tumour necrosis factor-alpha (TNF-α) receptors have inhibitory properties against TNF-α. The relative ratio between ligand and ligand inhibitors may influence the outcome of meningococcaemia. To test this hypothesis, levels of TNF-α and of each of the soluble inhibitory fragments originating from two distinct TNF-α receptors (sTNF-RI and sTNF-RII) were measured in sera of children with severe meningococcaemia. On admission to the hospital the levels of sTNF-RI, -RII and TNF-α were markedly increased and all three correlated with the outcome of the disease. A correlation was found between TNF-α and sTNF-RI (P < 0.001 by Pearson rank correlation coefficient) or sTNF-RII (P=0.012). For TNF-α concentrations below 500 pg/ml, the increase of TNF-α was proportional to that of sTNF-RI and RII; however, when TNF-α levels exceeded 500 pg/ml, sTNF-RI and RI1 concentrations did not increase proportionally. At admission, in patients with fatal outcome, thc ratios TNF-α/sTNF-RI and -RII were higher than in survivors. During the first 6 hr, the kinetics of TNF-α, sTNF-RI and -RII were different. Naturally occurring TNF-α inhibitors may play an important role in modulating the biological activity of TNF-α in severe meningococcacmia. [ABSTRACT FROM AUTHOR]

Exposure of human monocytes in monolayer culture to concanavalin A (Con A) or Fc fragments of IgG results in decreased levels of lysozyme, acid phosphatase and the second component of complement (C2), but increased levels of prostaglandin E2 (PGE2) in the culture medium. Indomethacin blocked the effect of Con A and Fc fragments on PGE2 levels but did not alter the effects on the other secretory products. The addition of Con A to the monocyte cultures resulted in increased cAMP levels in short (< 20 min) and in long term incubations (24 hr). Long term exposure to the Fc fragments of IgG also resulted in elevated levels of cAMP. In long term cultures, elevation of cAMP levels by Fc fragments and Con A may in part be mediated by stimulation of endogenous prostaglandin production, since addition of indomethacin resulted in a return of cAMP towards basal levels. The addition of D-L isoproterenol, IBMX, or exogenous PGE2, reagents that increase cAMP content, or addition of Dibutyryl 3′, 5′ adenosine monophosphate (DBcAMP) to cultures resulted in a dose-dependent inhibition of secretion of acid phosphatase, lysozyme and C2. These findings suggest that certain secretory responses of human monocytes are reduced by agents which increase cAMP levels. These changes may be related to direct effects on adenylate cyclase stimulation or indirect effects on the release of other products which effect cAMP generation. These changes in cAMP content may in part be responsible for the reduced secretory response. [ABSTRACT FROM AUTHOR]

A cell line (LLC-PK1) isolated from porcine kidney increases 3'5'-cyclic adenosine monophosphate (cAMP) content when incubated with salmon calcitonin (SCT) or antidiuretic hormone (ADH). We have examined several factors which modulate the hormone-induced changes in cAMP levels in these cells. Preincubation with increasing concentrations of SCT results in a dose-dependent decrease in cAMP levels in cells retested with this hormone. Addition of 3-isobutyl-l-methylxanthine (IBMX) to cells preincubated with SCT results in 15--30-fold increases in cAMP levels compared to cells preincubated without this hormone. These observations suggest that the decrease in SCT-induced cAMP response in cells pretreated with this hormone is related at least in part to stimulation of phosphodiesterase activity. Preincubation with ADH does not affect subsequent cAMP response to either ADH or SCT, suggesting that these hormones interact with different cell surface receptors. Cell cycle and plating density also affect cAMP levels. cAMP content per cell increases with increasing cell density, which is associated with an increase in the SCT-induced cAMP response. These studies illustrate that factors other than receptor occupancy modulate cAMP responses of these cells to specific hormones. [ABSTRACT FROM AUTHOR]

The objective was to study the relationship between the levels of interleukin-1 receptor antagonist (IL-1Ra) and disease activity and the acute-phase response in SLE patients with and without renal involvement. Twenty SLE patients who had distinct active clinical manifestations (eight glomerulonephritis, four systemic vasculitis without kidney involvement, nine skin rash, 12 arthritis, five serositis, four neuropsychiatric manifestations, three thrombocytopenia, one myositis and one haemolytic anaemia) were studied during a period of 8-12 months. Serum and plasma samples were taken at intervals of 6 weeks-4 months and tested for IL-1Ra, IL-1 beta, IL-6, IgG and anti-dsDNA, Clq, C3, C4 and C-reactive protein (CRP). IL-1Ra serum concentrations were increased in most SLE patients with active disease when compared to normal blood donors. However, at the time of flare, significantly higher levels of IL-1Ra were observed in patients with extra-renal disease as compared to other patients (median [range]: 363 [202-3041] and 4847 [268-27180] pg/ml for patients with and without renal involvement, respectively). This difference was not due to proteinuria. IL-1Ra levels did not correlate with SLEDAI score during flares, but they were elevated during flares in patients with extra-renal manifestations. When disease activity was at its highest, IL-1Ra concentrations correlated with IL-1 beta (r = 0.76; P < 0.001), IL-6 (r = 0.60; P < 0.01) and CRP (r = 0.61; P < 0.01), but not with C1q, C3, C4 and anti-dsDNA levels. The study showed that the pattern of inflammatory cytokines in active SLE varies in a manner that is dependent on which organs are involved. A relative absence of IL-1Ra response appears to be a feature characteristic of kidney involvement. IL-1Ra elevation clearly correlates with flares involving other organs. [ABSTRACT FROM PUBLISHER]

ANCA are found in various systemic vasculitis and are supposed to play a role in the pathogenesis of the disease, in cooperation with other factors such as cytokines. A total of 36 ANCA-positive and 10 ANCA-negative serum samples were analysed for the presence of TNF soluble receptors (TNF-sR), which are shed from the surface of activated cells and may act as TNF inhibitors. Of the ANCA-positive samples, 67% had elevated TNF-sR75 and 72% had elevated TNF-sR55 compared to ANCA-negative specimens (mean [S.E.] 18.7 [17.3] 3.6 [1.5] and 10.5 [9.7] 1.9 [0.7] ng/ml, <0.01). Elevation of TNF-sR in patients with ANCA suggests that cytokines and their inhibitors are involved in the pathogenesis of ANCA-associated autoimmune diseases. [ABSTRACT FROM PUBLISHER]

Tumour necrosis factor-alpha (TNF-α) is involved in diverse biological processes including immune and inflammatory reactions and the response to surgical stress. Two soluble TNF receptor protein fragments. TNF-sR55 (from the p55 kD TNF receptor) and TNF-sR75 (from the p75 kD TNF receptor), are released by cells during inflammation and may modulate the effects of TNF-α. We have studied the kinetics of secretion of TNF-α. TNF-sR55 and TNF-sR75 in the sera of patients with rheumatoid arthritis (RA) and control subjects with osteoarthritis (OA) or chronic osteomyelitis (OM) before and after major surgery. Significantly higher pre-operative levels of TNF-sR55 and TNF-sR75 were found in RA and OM as compared with OA (P<0.02). Following surgery. TNF-sR55 increased within 24 min RA.OM and OA(P<0.05). whereas TNK-sR75 increased significantly only in OM and OA patients (P<0.05). By contrast, no TNF-α was detectable before and after surgery in any of the subjects, but this may have been due to impaired detection (by ELISA) of TNF-α when it is bound to TNF-sR. These findings suggest that TNF-sR55 and TNF-sR75 may be further markers of the host's reaction to inflammatory insults. They may also play a role in modulating the immune and inflammatory reactions by inhibiting the systemic effects of TNF-α. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor alpha (TNF-α) plays an important role in microbial defence and tissue damage by activating neutrophils. Therefore the ability of natural molecules to regulate the activity of TNF-α, is likely to be of major importance in our understanding of the mechanisms of inflammation. We have examined the effects of a highly purified urine-derived TNF inhibitor (TNF inh) on the TNF-α-induced respiratory burst in human neutrophils. TNF-α inh-treated TNF-α was unable to stimulate a neutrophil lucigenin-dependent chemiluminescence response and superoxide formation. Treatment of TNF with the inhibitor also significantly reduced the priming ability of TNF-α for a response to the peptide f-met-leu-phe. These results show that the ability of TNF-α to induce a key neutrophil response is amenable to regulation by the TNF-α inh. [ABSTRACT FROM AUTHOR]