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)

Polymorphonuclear leukocytes (PMN) are known to be activated by several lymphokines and can be induced to release lysosomal enzymes, prostaglandins (PG), thromboxanes (TX) and lipoxygenase products that may be involved in PMN aggregation responses during inflammatory reactions. Granulocyte-macrophage colony stimulating factor (GM-CSF), a glycoprotein cytokine released by immunocompetent cells, has been found to prime neutrophil responses, such as increased cell aggregation after exposure to various biological stimulants. In this study, we examined the effects of the cytokine GM-CSF on human neutrophilic aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) and its influence on the production of various arachidonic acid metabolites. Neutrophil aggregation of purified PMNs was measured by the percent change in light transmission in a standard aggregometer, and the arachidonic acid products leukotriene B4 (LTB4) and thromboxane A2 (TXA2) were quantified by radioimmunoassay. We found that GM-CSF and other cytokines, used alone, did not cause any significant increase in aggregation of the PMN. However, prior exposure of PMN to GM-CSF markedly increased the aggregation induced by FMLP as opposed to that detected with PMN stimulated with only FMLP. This priming effect was not observed with PMN preincubated with interleukin-1 (IL-1), tumor necrosis factor (TNF) or interleukin-6 (IL-6). In addition, GM-CSF and IL-6 both failed to stimulate the production of LTB4 and TXA2, products which are known to induce PMN aggregation. These findings provide new evidence suggesting that GM-CSF facilitates the action of FMLP on the adhesion dependent cellular functions of the inflammatory response, serving as an important co-factor in neutrophil aggregation.
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PMID:Granulocyte-macrophage colony stimulating factor potentiates human polymorphonuclear leukocyte aggregation responses to formyl-methionyl-leucyl-phenylalanine. 132 27

Cytosolic aminopeptidase P was obtained in highly purified form from human leukocytes by a four-step procedure. Buffy coats were the starting material. A M(r) of 140,000 was obtained by size-exclusion HPLC for the native enzyme. As shown by SDS/PAGE under reducing and denaturing conditions, the enzyme consisted of likely identical subunits with M(r) of 71,000. Purified aminopeptidase P cleaved off, specifically and efficiently, the N-terminal residues from peptides with N-terminal Xaa-Pro sequences. The penultimate proline was not replaceable by hydroxyproline, alanine and glycine in di-, tri- and tetrapeptides. Polyproline was not hydrolyzed. Dipeptides were cleaved (Arg-Pro, Phe-Pro > Trp-Pro > Pro-Pro) although slower than longer peptides. Cleavage was observed of several biologically active peptides; C-terminal fragment (residues 201-206) of C-reactive protein, oxytocin fragment Tyr-Pro-Leu-Gly, morphiceptin, peptide Gly-Pro-Arg-Pro (inhibitor of fibrin polymerization) and kentsin. In addition, cleavage of a protein, interleukin-6, was also demonstrated. Aminopeptidase P was maximally activated by Mn2+, and to a lesser extent by Co2+. The activity was optimal at pH 8. Ni2+, Zn2+ and especially Cd2+ caused marked inhibition. EDTA, 1,10-phenantroline and dithiothreitol were also inhibitory. Carbobenzoxy-phenylalanine, as well as several N-carbobenzoxy-proline-containing peptides, caused partial inhibition. The observed resistance of Gly-Pro, Pro-Gly, Pro-Phe and Pro-Ile to hydrolysis by the purified enzyme strongly indicates absence of known proline-specific dipeptidases in the aminopeptidase-P preparation.
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PMID:Aminopeptidase P from human leukocytes. 144 89

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli-derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.
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PMID:Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. 169 93

Cell lines of human fibroblasts from primary cultures released reactive oxygen species, and displayed an increase in low-level chemiluminescence when stimulated with serum-treated zymosan, N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4, or 12-O-tetradecanoylphorbol 13-acetate, all of which are known stimulants of respiratory burst in phagocytic cells. Non-serum-treated zymosan, interleukin-6, interleukin-2, interferon-gamma or complement factor C3b were ineffective. The primary radical species produced was O theta.2. Radical formation was continuous for up to 4 h, and it did not occur as an oxidative burst. The low level chemiluminescence probably arose from the excitation of carbonyl groups, since it remained unchanged in the presence of azide and 1,4-diazabicyclo[2.2.2]octane. While the release of reactive oxygen species in phagocytes has a function in defense mechanisms, the sustained production of such species in tissue cells may have a role in signaling mechanisms. The amounts of reactive oxygen species released by the fibroblasts upon stimulation with the stimulants mentioned above were low in comparison with the known stimulatory effects of cytokines [Meier et al. (1989) Biochem. J. 263, 539-545].
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PMID:Human fibroblasts release low amounts of reactive oxygen species in response to the potent phagocyte stimulants, serum-treated zymosan, N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4 or 12-O-tetradecanoylphorbol 13-acetate. 196 84

Murine interleukin-6 (mIL-6) was expressed in Escherichia coli in the insoluble fraction of cell lysates. Approximately equal amounts of two polypeptide species, reactive with anti-IL-6 antibodies, were produced. The two forms of mIL-6 were isolated and found to have identical N-terminal sequences initiated by Met-Phe-Pro-Thr-Ser-Gln-. Peptide mapping after endoproteinase glu-C digestion led to isolation and characterization of the C-terminal peptides from each of the two forms and allowed the source of the heterogeneity to be identified as a C-terminal addition of three amino acids, Gln-Lys-Leu, to authentic mIL-6. Inspection of the nucleotide sequence of the plasmid containing the mIL-6 gene and expression of the plasmid in other strains suggested that the addition of three amino acids was caused by a readthrough of the termination codon arising from an unexpected suppressor mutation in the original host strain. Although the C-terminus of IL-6 is critical for the activity of this cytokine, the IL-6 variant with extended C-terminus was fully active in two separate bioassays. This suggests that the additional amino acids do not disrupt the structure or function of this important region of the molecule.
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PMID:Identification and characterization of a C-terminally extended form of recombinant murine IL-6. 203 66

BSF-2 (B cell stimulatory factor-2/IL-6) is a member of the lymphokine family and responsible for B cell differentiation. Expression plasmids of human BSF-2 cDNA were constructed using a trp promotor/operator and a trpA terminator. In an extract of Escherichia coli HB101 holding "direct" expression plasmid pBSF-2D, activity of BSF-2 was detected, but overproduction was not observed. A "fused" expression system was therefore developed to prepare the recombinant protein. In this system, cDNA was expressed as a fused protein with human IL-2 N-terminal peptide. In the case of the fused BSF-2 expression plasmid, pBSF-2F, inclusion bodies were observed and overproduction of the protein occurred. As this fused protein had a Phe-Arg-Ala sequence at the junction of hIL-2 and BSF-2, it was possible to process mature BSF-2 from the fused BSF-2 by treatment with kallikrein and aminopeptidase P. From 1 liter of E. coli culture, 45 mg of mature BSF-2 was purified; it had a relative biological activity equal to that of natural BSF-2 purified from T cells.
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PMID:High-level expression of human BSF-2/IL-6 cDNA in Escherichia coli using a new type of expression-preparation system. 285 86

The present study was undertaken to examine the effects of bradykinin and selected bradykinin analogues on mononuclear cells derived from mouse spleen. Bradykinin as well as des-Arg9-bradykinin, a bradykinin B1 receptor agonist, were able to induce the release of so-called charge-changing lymphokines, which could be identified as interleukin-1, interleukin-6, interleukin-2 and as interleukin-2 receptor. The cytokine release evoked by bradykinin and all analogues showed a bell-shaped dose dependence in a range of 10(-8) M to 10(-6) M and could be inhibited by the specific bradykinin receptor antagonist, D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE140), and by bradykinin analogues with N-methyl-phenylalanine at position 2 in concentrations as low as 10(-12) M and 10(-13) M, respectively. Obviously the N-terminus of bradykinin seems to be responsible for the interaction with the mononuclear cells concerning all peptides investigated.
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PMID:Effects of bradykinin and bradykinin analogues on spleen cells of mice. 755 3

Endothelin-1 (ET-1) is a vasoconstrictive peptide released by ischemic/injured endothelium which increases intracellular ionized calcium [Ca2+]i in vascular smooth muscle. Previous work from this lab has shown that ET-1 also increases human peripheral blood monocyte [Ca2+]i, and that 24 h incubation of monocytes with 10(-9) M ET-1 causes production of prostaglandin E2 and interleukin-6. In these studies, ET-1-stimulated monocyte supernatants were evaluated for their effect on neutrophil superoxide production. While ET-1 alone had no direct effect, incubation of neutrophils for 20 min in ET-1-stimulated monocyte supernatants resulted in a 10-fold increase in superoxide production over basal levels, 44% as much superoxide production as induced by peptide N-formyl-methionyl-leucyl-phenylalanine (N = 6, p < .001). Monocyte supernatants were analyzed for interleukin-8 (IL-8 or neutrophil activation protein) content by radioimmunoassay. ET-1-stimulation resulted in production of 54% as much IL-8 as lipopolysaccharide controls (N = 6, p < .001). While a number of monokines can activate neutrophils, IL-8 has been shown to be a potent neutrophil activator as well as a superoxide primer. Therefore, ET-1-treated monocytes probably upregulate neutrophil superoxide production via a mechanism which includes IL-8.
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PMID:Endothelin-stimulated monocyte supernatants enhance neutrophil superoxide production. 773 49

Despite much research, the pathophysiology underlying lower L-tryptophan (L-TRP) availability in major depression has remained elusive. The present study investigates whether lower L-TRP availability in major depression is related to immune activation which may occur in that illness and is known to modulate L-TRP metabolism. Toward this end, the authors have measured the following in depressed patients and normal control subjects: plasma levels of L-TRP, and the competing amino acids (CAA) valine, leucine, isoleucine, tyrosine, and phenylalanine, together with indices of immune function such as haptoglobin (Hp) and transferrin (Tf) plasma levels, dipeptidyl peptidase IV (DPP IV) serum activity, and mitogen-induced culture supernatant interleukin-6 (Il-6) production. Both plasma levels of L-TRP and the L-TRP/CAA ratio were significantly lower in major depressed subjects as compared with healthy control subjects. There were significant correlations between plasma L-TRP levels, on the one hand, and Tf plasma levels, DPP IV activity (both positive), Il-6 production, and Hp plasma levels (both negative), on the other. Up to 63.7% of the variance in L-TRP plasma concentrations could be explained by DPP IV, Hp, Il-6 values, and gender. Up to 50% of the variance in the L-TRP/CAA ratio could be explained by Hp values (negative correlation) and gender. It is hypothesized that lower plasma L-TRP availability in major depression may be related to the immune response in that illness.
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PMID:Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. 790 45

Mice of the C57BL/6 strain were injected with bacterial lipopolysaccharide (LPS) followed by formylnorleucyl-leucyl-phenylalanine (FNLP) by the intraperitoneal route; markers of acute lung injury were examined in mice given a fusion protein of soluble human tumor necrosis factor-alpha (TNF-alpha) receptor (p80) linked to the Fc portion of human IgG (TNFR:Fc) or excipient. Challenge with LPS/FNLP elicited an adult respiratory distress syndrome-like pathology characterized by sharp increases in levels of lactate dehydrogenase (LDH) and total proteins in bronchoalveolar lavage as well as in lung myeloperoxidase (MPO) content at 16 and 20 h after challenge. Infusion of 1 mg of TNFR:Fc 2 h before challenge very significantly abrogated the increases in LDH, protein levels, and MPO. Histologic analysis revealed that LPS/FNLP infusion resulted in an intravascular neutrophil agglomerate and perivascular/peribronchial damage; the extent of tissue lesions was significantly reduced, but not abrogated, by TNF-alpha depletion. There were moderate levels of antigenic TNF-alpha in lung homogenates at 16 and 20 h after challenge, not affected by infusion with TNFR:Fc. No bioactive TNF-alpha was detected in lung homogenates of challenged mice given TNFR:Fc. High levels of antigenic interleukin-6 (IL-6) were found in lung homogenates of challenged mice treated with TNFR:Fc or with diluent. Elevated levels of antigenic IL-6 and TNF-alpha were found in sera of challenged mice at 16 and 20 h after injection; TNFR:Fc-treated mice had a higher level of antigenic TNF-alpha than did challenged mice given diluent, but it was not bioactive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A mouse model of lung injury induced by microbial products: implication of tumor necrosis factor. 800 42


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