Interleukin-6 peptides

F. Interleukins — peptides which transfer signals between white blood cells. In this they are helped by interferons (which are growth inhibitors), tumour necrosis factor (TNF), the CSFs and TGF-/3. 

Cytokines (e.g., interleukins Peptides 1-18, tumor necrosis factor, interferons)... 

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Gendelman HE, Persidsky Y (2005) Infections of the nervous system. Lancet Neurol 4 12-13 Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2 108-115 Gitter BD, Cox LM, Rydel RE, May PC (1995) Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proc Natl Acad Sci USA 92 10738-10741 GiuUan D, Yu J, Li X, Tom D, Li J, Wendt E, Lin SN, Schwarcz R, Noonan C (1996) Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocytes found in human brain. J Neurosci 16 3139-3153... 

These are supplied by the secretion of peptide molecules (termed cytokines or lymphokines) fiom a subset of the T-cell family (the helper T cells, TH cells). These peptide molecules (interleukins (IL) 2,4,5 and 6) stimulate the B cells to proliferate, undergo clonal expansion and mature into plasma cells which secrete antibody and also into the longer-hving, non-dividing memory cells. 

Amino acid receptors Monoamine receptors Lipid receptors Purine receptors Neuropeptide receptors Peptide hormone receptors Chemokine receptors Glycoprotein receptors Protease receptors Metabotropic glutamate and GABAb receptors Adrenoceptors, dopamine and 5-HT receptors, muscarinic and histamine receptors Prostaglandin, thromboxane and PAF receptors Adenosine and ATP (P2Y) receptors Neuropeptide Y, opiate, cholecystokinin VIP, etc. Angiotensin, bradykinin, glucagon, calcitonin, parathyroid, etc. Interleukin-8 TSH, LH/FSH, chorionic gonadotropin, etc. Thrombin... 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

More recently, free radicals have been postulated to mediate part of the beta cell cytotoxicity of interleukin-1 (IL-1), a peptide hormone produced by macrophages. 

Katancik JA, Sharma A, de Nardin E. Interleukin 8, neutrophil-activating peptide-2 and GRO-alpha bind to and elicit cell activation via specific and different amino acid residues of CXCR2. Cytokine 2000 12(10) 1480-1488. 

Schroder JM, Mrowietz U, Morita E, Christophers E. Purification and partial biochemical characterization of a human monocyte-derived, neutrophil-activating peptide that lacks interleukin 1 activity. J Immunol 1987 139 3474-3483. 

Koch AE, Volin MV, Woods JM, et al. Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum 2001 44(1) 31 40. 

Moser B, Schumacher C, von Tschamer V, Clark-Lewis I, Baggiolini M. Neutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils. J Biol Chem 1991 266(16) 10666-10671. 

Reported applications of SASD involve modification of lipopolysaccharide (LPS) molecules and studying their interaction with albumin and an antibody directed against LPS (Wollenweber and Morrison, 1985), identification of the murine interleukin-3 receptor and an N-formyl peptide receptor (Sorenson et al., 1986), crosslinking of factor V and Va to iodinated peptides... 

Tsudo, M., Kozak, R.W., Goldman, C.K., and Waldmann, T.A. (1987) Demonstration of a non-Tac peptide that binds interleukin 2 A potential participant in a multichain interleukin 2 receptor complex. Proc. Natl. Acad. Sci. USA 83, 9694-9698. 

IL-la and -ip are expressed as large (30 kDa) precursor molecules from which the mature polypeptide is released by proteolytic cleavage. Neither IL-la and -lp possess any known secretory signal peptide, and the molecular mechanism by which they exit the cell remains to be characterized. Neither interleukin appears to be glycosylated. 

The neurohormonal model of HF recognizes that an initiating event (e.g., acute MI) leads to decreased cardiac output but that the HF state then becomes a systemic disease whose progression is mediated largely by neurohormones and autocrine/paracrine factors. These substances include angiotensin II, norepinephrine, aldosterone, natriuretic peptides, arginine vasopressin, proinflammatory cytokines (e.g., tumor necrosis factor a, interleukin-6 and interleukin-1 ft), and endothelin-1. 

While the majority of attention has focused on peptides contained within the nervous system, two other important methods for delivering peptides to the vicinity of the mast cell have been established (1) peptides produced and secreted by other cells of inflammation that may affect mast-cell function and (2) the local generation of mast-cell-active peptides by secreted enzymes acting on circulating protein precursors. Examples of the former include several, as yet ill-defined, peptide factors and cationic proteins from other immunocompetent cells [66-69], defined lymphokines such as the interleukin-1 [70] and interleukin-3 [71], and tumour necrosis factor [70], Examples of the latter include bradykinin [72] and a recently identified peptide produced by the action of acid proteinases on albumin [73, 74]. 

Interleukin-1 (IL-1) produced by monocytes and several other cell types [70, 146] has a wide array of biological properties, including T cell activation and inflammatory interactions with muscle, liver, fibroblasts, brain and bone [70, 146], IL-1, both natural and recombinant, has been shown to release histamine from human basophils and from human adenoidal mast cells [70,146,151] and this release was abolished by an IL-1 antibody. However, the average release produced by 10 units of IL-1 was less than 20% and there was considerable variability between populations of basophils in the extent of histamine release. Moreover, the secretory response elicited was quite slow (within 15 min) compared with that of other peptides [151]. Desensitization of the basophils by anti-IgE serum had no effect on the subsequent IL-1 response, suggesting different mechanisms of action [ 151], as has been the case with other peptides. Interestingly, the portion of the IL-1 molecule that is responsible for its immu-nostimulatory activity appears to be separate from that portion responsible for its proinflammatory effects [152]. However, that portion of the molecule responsible for eliciting basophil and mast-cell histamine release has not as yet been defined. 

R. A. Kenley, N. W. Warne, Acid-Catalyzed Peptide Bond Hydrolysis of Recombinant Human Interleukin 11 , Pharm. Res. 1994, 11, 72-76. 

Caspase-l [EC 3.4.22.36] (also known as interleukin-lj8 converting enzyme and interleukin-1/3 convertase precursor) is a member of the peptidase family C14. It catalyzes the hydrolysis of the Asp -Ala and Asp -Gly in the precursor protein, resulting in the release of interleukin-ljS. The enzyme will also hydrolyze the small peptide, Ac-TyrValAlaAsp—NHMEC. 

Interleukin 8 (IL-8) Neutrophil-activating peptide 2 Platelet factor IV... 

Thymosin is an immunomodulatory peptide produced by the thymus gland and other cells. Thymosin alfa 1, a 28-amino acid peptide, is one member of the family of thymosins that collectively appear to influence a variety of regulatory and counter-regulatory functions in terms of T-cell maturation and antigen recognition, stimulation of native interferons and cytokines such as interleukin-2, and activity of natural killer cell-mediated cytotoxicity. In some countries it is approved as an adjuvant for influenza vaccine or as a treatment for chronic hepatitis B and, in combination with interferon for hepatitis C. Thymosin alfa 1 has been used with some success to treat children with the severe form of Di-George Syndrome. 

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