Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study sought to determine whether endogenous tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and granulocyte-colony-stimulating factor (G-CSF) were detectable in sera of lipopolysaccharide (LPS)-treated cancer patients. Twenty patients received an intravenous bolus of purified LPS from Salmonella abortus-equi (4.0 ng/kg). Patients were pretreated with ibuprofen (1,600 mg) to prevent constitutional side effects like fever and chills. Serum TNF-alpha levels increased from less than 0.01 ng/ml before treatment up to maximal levels of 21 ng/ml, peaking 1.5 h after LPS injection. Similarly, serum IL-6 concentrations increased from less than 0.01 to 11 ng/ml, but peak levels were obtained 30 min later than TNF-alpha. Circulating G-CSF appeared still later than TNF-alpha and IL-6. It was detectable within 3 h and peaked 6 h after LPS injection. Parallel to the release of the above cytokines a marked increase in granulocyte counts was observed. In all patients administration of LPS led to an acute-phase response as measured by C-reactive protein.
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PMID:Treatment of cancer patients with endotoxin induces release of endogenous cytokines. 171 15

Intravenous (IV) administration of purified lipopolysaccharide (LPS) from Salmonella abortus equi to cancer patients induces the formation of high amounts of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). On repeated administration of LPS at 2-week intervals, a marked downregulation of the cytokine response was observed, especially between the first and the second challenge. This study sought to determine whether it would be possible to prevent this downregulation by pretreating patients with interferon-gamma (IFN-gamma), which is known to enhance cytokine production by monocytes and macrophages in vitro. Ten patients with disseminated cancer received a first injection of 4.0 ng LPS/kg. Thereafter, patients were divided into two groups. One group received two further LPS injections (4.0 ng/kg) at 2-week intervals. The second group was pretreated (-12 hours) with 50 micrograms IFN-gamma subcutaneously (SC) before the second and third LPS challenge. To prevent constitutional side effects such as fever and chills, patients received 1,600 mg ibuprofen orally before LPS injection. The results of the current study demonstrate that apart from TNF-alpha and IL-6, two other cytokines, interleukin-8 (IL-8) and granulocyte colony-stimulating factor (G-CSF) are produced in cancer patients in response to LPS. LPS application at 2-week intervals resulted in a transient attenuation of all cytokines (TNF-alpha, IL-6, IL-8, G-CSF) on the second challenge. In the case of TNF-alpha, IL-6, and G-CSF, pretreatment with IFN-gamma not only prevented the downregulation, but enhanced the production of these cytokines to levels higher than those obtained after the first LPS challenge. In contrast, the downregulation of IL-8 remained unaffected by IFN-gamma pretreatment. Further studies are warranted to determine whether the prevention of cytokine downregulation by IFN-gamma following repeated LPS injections is of clinical relevance in respect to the antitumor activity of LPS.
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PMID:Modulating activity of interferon-gamma on endotoxin-induced cytokine production in cancer patients. 172 Jul 1

The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS from Salmonella abortus equi was administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C-reactive protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor-alpha (TNF) and interleukin-1 beta serum levels were measured by enzyme-linked immunosorbent assay and interleukin-6 (IL-6) by bioassay. Dose-limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels greater than 8.0 ng/kg of body weight (MTD-2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL-6 serum concentrations increased from less than 4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above-mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15-10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL-6 increased in a dose-dependent manner although the constitutional symptoms are completely attenuated.
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PMID:Biological response to intravenously administered endotoxin in patients with advanced cancer. 225 60

Although the clinical effects of acute exposure to ultraviolet (UV) light--such as cutaneous inflammation, malaise, somnolence, chills and fever--have been appreciated many years, the underlying mechanisms mediating these effects are poorly understood. Interleukin-6 (IL-6) is a potent cytokine with a wide variety of biologic activities, including induction of fever and acute phase response. Because IL-6 is produced by keratinocytes in vivo and in vitro and because the release is enhanced by UV light, the present study was performed to investigate the effect of a single UV dose eliciting moderate to severe sunburn reaction on the production of IL-6 in vivo. Therefore, plasma of UV-treated human subjects was evaluated for IL-6 activity by testing its capacity to induce the proliferation of an IL-6-dependent hybridoma cell line (B9). In contrast to plasma samples obtained before UV exposure, post-UV-specimens contained significant levels of IL-6 peaking at 12 h after UV irradiation. Plasma IL-6 activity was neutralized by an antiserum directed against recombinant human IL-6, and upon HPLC gel filtration exhibited a molecular weight of around 20 kD. Moreover, plasma IL-6 levels correlated remarkably with fever course followed by an increase of acute phase proteins such as C-reactive protein. These data indicate that IL-6, which is released by keratinocytes following UV exposure, may gain access to the circulation and via its pyrogenic as well as acute phase-inducing effect may function as an important mediator of systemic sunburn reaction.
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PMID:Ultraviolet light induces increased circulating interleukin-6 in humans. 235 83

Eighteen patients were treated with escalating doses of recombinant, Escherichia coli-derived human interleukin-6 (IL-6) intravenously every 8 h. Therapy was given for two cycles of 7 days each separated by a week off therapy. Fevers and chills were observed in most patients. Mild renal and liver function abnormalities were noted at higher doses of IL-6. Dose-limiting toxicity was reached at 30 micrograms/kg i.v. every 8 h due to reversible neurotoxicity, but significant rapidly reversible anemia and hyperglycemia were seen at lower doses. Platelet counts, white blood cell counts, and acute phase reactant levels were substantially elevated. No antitumor responses were seen. A maximum tolerated dose of 10 micrograms/kg i.v. every 8 h for two 7-day cycles is recommended for future phase II trials.
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PMID:A phase I trial of intravenous interleukin-6 in patients with advanced cancer. 752 Mar 34

As procalcitonin concentrations have been shown to be elevated in patients with septicemia and gram-negative infections in particular, we proceeded to investigate the effect of endotoxin, a product of gram-negative bacteria, on procalcitonin concentrations in normal human volunteers. Endotoxin from Escherichia coli 0113:H10:k, was injected i.v. at a dose of 4 mg/kg BW into these healthy volunteers. Blood samples were obtained before and 1, 2, 4, 6, 8, and 24 h after injection of the endotoxin. Each patient's cardiovascular and overall clinical status was monitored over this period. The patients developed chills and rigors, myalgia, and fever between 1-3 h. Tumor necrosis factor-alpha levels increased sharply at 1 h and peaked at 90 min, reaching the baseline concentration thereafter by 6 h. Interleukin-6 levels increased more gradually, peaking at 3 h and reaching the baseline concentration at 8 h. The procalcitonin concentration, which was undetectable (< 10 pg/mL) at 0, 1, and 2 h, was detectable at 4 h and peaked at 6 h, maintaining a plateau through 8 and 24 h (4 ng/mL). There was no elevation of calcitonin concentrations, which remained below 10 pg/mL, the lowest sensitivity of the assay. Procalcitonin was measured by a two-antibody immunoradiometric assay specific for this peptide, with no cross-reactivity with calcitonin, katacalcin, or calcitonin gene-related peptide. We conclude that endotoxin induces the release of procalcitonin systemically, that this increase is not associated with an increase in calcitonin, and that the increase in procalcitonin associated with septicemia in patients may be mediated through the effect of endotoxin described here. Whether procalcitonin participates in the mechanisms underlying inflammation remains to be investigated.
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PMID:Procalcitonin increase after endotoxin injection in normal subjects. 798 63

Eighteen advanced cancer patients received weekday subcutaneous injections of recombinant interleukin-6 (rIL-6) for 4 weeks at escalating doses. Patients were evaluated for hematologic and immune system effects. Hematologic monitoring included WBC, differential, Hgb and Hct, platelet counts, and assessment of marrow and peripheral blood progenitors. Immunologic monitoring included evaluation of acute-phase reactants (APRs), immunophenotyping, serum cytokine levels, cytokine-induced proteins, and cytokine messenger RNA (mRNA). The maximal tolerated dose (MTD) was 8.0 micrograms/kg/day, with neurocortical toxicity as the major limiting factor. All patients became anemic, and most had fever and chills. APRs were increased throughout treatment. WBCs increased transiently on day 2; granulocytes and monocytes increased again through day 26, whereas lymphocytes decreased to baseline or lower levels. Platelets responded by day 12 and increased through day 26 at the MTD with no effect on colony-forming unit-megakaryocyte (CFU-Mk). Peripheral WBC and RBC progenitors were not affected but decreased in the marrow. T-cell percentages declined with little effect on absolute numbers; T-cell activation was seen. CD45RO+ T cells decreased, but there was no significant effect on CD8+ CD28+ T cells. Neither B cells nor natural killer (NK) cells were affected. However, evidence of monocyte effects included upregulation of CD71, induction of the cytokine-induced proteins 2-5A synthetase and neopterin, and increases in tumor necrosis factor-alpha (TNF-alpha) mRNA. Serum cytokines were undetected, and mRNA for IL-1 beta, IL-2, and interferon-gamma (IFN-gamma) was not induced; however, mRNA for IL-4 and IL-10 did increase suggesting activation of Th2-like T cells. One mixed tumor response was seen. We conclude that IL-6 alone has systemic activity on the immune system, as well as the hematopoietic system, which at the MTD, primarily involves induction of APR, activation and expansion of monocytes, and activation of Th2-like T cells.
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PMID:Hematologic and immunologic evaluation of recombinant human interleukin-6 in patients with advanced malignant disease: evidence for monocyte activation. 881 98

The relation between gram-negative bacteremia, endotoxemia and cytokinemia in patients with hematological malignancies was studied. Serum endotoxin and cytokines (tumor necrosis factor-alpha, interleukin-1 receptor antagonist, interferon-gamma, interleukin-6 and interleukin-10) were determined in 24 patients with hematological malignancies. Patients were included at start of fever (n = 18) or during a temperature peak during continuous fever (n = 6; time = 0). Blood was drawn for cultures at time of inclusion. Additional samples were obtained and grouped in two time intervals (1-5 h and 6-12 h after inclusion). Endotoxin was detected in eight patients. Endotoxemia was more common among patients with bacteremia than among non-bacteremic patients (7/12 versus 1/12; p < 0.05). All studied cytokines showed a tendency to higher mean values at time 0 in patients with endotoxemia than in patients without endotoxemia. Significantly higher mean endotoxin values were seen at time 1-5 h in patients with gram-negative bacteremia (n = 6) than in patients without gram-negative bacteremia, and at time 0 in patients with chills (n = 6) compared to those without chills.
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PMID:Endotoxemia in febrile patients with hematological malignancies. Relationship of type of bacteremia, clinical findings and serum cytokine pattern. 903 29

We examined the tolerability and safety of interleukin-6 (rhIL-6) when administered prior to and concurrent with vincristine, doxorubicin and dexamethasone (VAD) in patients with progressive multiple myeloma previously treated with VAD alone. Typical rhIL-6-related effects such as fever, chills, acute phase reactions and reversible abnormalities in liver function tests were observed. The study examined whether rhIL-6 predictably modulated indices of myeloma activity. No consistent, predictable change in myeloma-related parameters was documented upon rhIL-6 administration for either 8 days or 11 days prior to and concurrent with VAD. Two patients showed improved sensitivity to VAD chemotherapy when this was administered with rhIL-6. The overall response rate to rhIL-6 and VAD therapy in this study of relapsed and refractory patients was 50%, comparable to our previous experience with VAD alone in this cohort of patients.
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PMID:Phase II trial of rhIL-6 (interleukin-6) prior to and concurrently with VAD (vincristine, doxorubicin and dexamethasone) chemotherapy for patients with multiple myeloma. 913 7

MDX-H210 is a chemically, cross-linked, half-humanized bispecific antibody composed of F(ab') fragment from monoclonal antibody (mAb) H22 that binds to the high-affinity receptor Fc gamma RI and F(ab') of mAb 520C9 that recognizes the erbB-2 (HER2/neu) oncoprotein. In a previous trial, the murine bispecific, MDX-210 at a dose of 7 mg/m2, was well tolerated and activated monocytes and macrophages in vivo in doses as low as 0.35 mg/m2. In our multidose trial, granulocyte-macrophage colony-stimulating factor, which increases and activates potential effector cells, was given on days 1-4 at 250 micrograms/m2 s.c. and MDX-H210 was given on day 4 weekly for 4 consecutive weeks. Thirteen patients were treated at dose levels of 1, 3.5, 7, 10, 15, and 20 mg/m2 without dose-limiting toxicity. Fever, chills, and rigors occurred during and up to 2 h postinfusion and correlated with the time to peak levels of tumor necrosis factor-alpha (median 88.2 pg/ml; range 15.6-887 pg/ml) and interleukin-6 (median 371 pg/ml; range 175-2,149 pg/ml). By the fourth consecutive week of treatment the side effects and cytokine levels decreased significantly. Human antibispecific antibody (HABA) levels were increased by 200- to 500-fold above pretreatment levels in 5 of 11 evaluable patients after 3 weeks of treatment. The monocyte and granulocyte population increased on days 4 and 11 (median 44%; range 18-68% and 42%; 19-71%), respectively, for monocytes and (60%; 43-75% and 74%; 54-82%) on days 4 and 11 for granulocytes. There was a significant decrease in the monocyte populations immediately after MDX-H210 administration (median decrease 73%; range 42-94%) and (52%; 12-72%) on days 4 and 11, respectively. Ten patients completed 4 weeks of treatment. One patient had a 48% reduction in an index lesions and six patients had stable disease at the time of evaluation. Three patients progressed before the fourth week. The therapy was generally well tolerated with toxicity, primarily, limited to the days of treatment.
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PMID:A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. 1040 39


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