《Minireviews - interleukin 6》由会员分享，可在线阅读，更多相关《Minireviews - interleukin 6（5页珍藏版）》请在金锄头文库上搜索。
1、MinireviewsInterleukin 6Date 1/1/1999First printed in R&D Systems 1999 Catalog.OverviewWhile a number of Interleukins such as Interleukin-1 (IL-1)1 and IL-102 are seemingly pleiotrophic in their effects, Interleukin 6 (IL-6) may be considered the prototypic pleiotrophic cytokine.3, 4 This is reflect
2、ed in the variety of names originally assigned to IL-6 based on function, including Interferon beta 2, IL-1-inducible 26 kD Protein, Hepatocyte Stimulating Factor, Cytotoxic T-cell Differentiation Factor, B cell Differentiation Factor (BCDF) and/or B cell Stimulatory Factor 2 (BSF2).3 Once all the a
3、ctivities associated with the various names for IL-6 became connected with one common gene, the actual name IL-6 was proposed for this molecule.5 A number of cytokines make up an IL-6 cytokine family. Membership in this family is based on a helical cytokine structure and receptor subunit makeup.6, 7
4、 For reviews on IL-6, see references 3, 4, 8-11.Figure 1. IL-6 and Acute Phase Proteins. SAA = Serum Amyloid Protein A. CRP = C-Reactive Protein.Structural InformationHuman IL-6 is a variably glycosylated, 22-27 kDa secreted glycoprotein that serves as a prototype for a family of molecules that incl
5、udes leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and IL-11. Although all molecules possess a similar helical structure, their association is due to their functional redundancy and receptor interactions.3, 6, 7, 11 IL-6 is translate
6、d as a 212 amino acid (aa) molecule, with a 28 aa signal sequence and a 184 aa mature segment.12-15 It contains four cysteines and two potential N-linked glycosylation sites with its primary structure showing limited homology to G-CSF.15 An alternate splice variant of IL-6 was identified in monocyte
7、s and lymphocytes.16 This form is 17 kDa and 148 aa long and appears to lack a binding site for the IL-6 signal transducing molecule gp130. A virally encoded form of IL-6 in human herpesvirus type 8 is 204 aa long and shows 25% aa identity to human IL-6.17, 18 While it is active on human cells, it i
8、s not clear if its binding properties are comparable to those of IL-6.18, 19 Mouse and rat IL-6 also have been cloned and are approximately 40% identical to human IL-6 at the aa level.20-22 Unlike human IL-6, mouse and rat IL-6 lack potential N-linked glycosylation sites, but may be O-glycosylated.2
9、0 The presence or absence of glycosylation, however, has no effect on bioactivity.ReceptorThe functional receptor for IL-6 is a complex of two transmembrane glycoproteins (gp130 and IL-6 receptor) that are members of the Class I cytokine receptor superfamily. Members of this family are defined by th
10、eir extracellular regions with at least two adjacent fibronectin type III domains that are often preceded by a C2-type Ig-like domain. Within the type III domains, one has four conserved cysteines, while a second shows a Trp-Ser-xxx-Trp-Ser (WSxWS) motif.6, 51 A number of cytokine receptor component
11、s belong to this superfamily, including LIF R, CNTF R alpha, IL-6 R alpha and gp130,6, 9 OSM R beta,52 IL-11 R alpha 53and CT-1 R alpha.54gp130/CD130:gp130 (or glycoprotein-130 kDa) is the signal transducing subunit of the functional IL-6 receptor (IL-6 R) complex. When membrane-bound, it can range
12、anywhere from 130-145 kDa, with the 145 kDa form representing the glycosylated “gp130”.55, 56 In humans, gp130 is 896 aa long, with a 597 aa extracellular region, a 22 aa transmembrane domain and a 277 aa cytoplasmic segment.56 In the extracellular region, there are six type III fibronectin domains
13、plus the expected WSxWS motif and four conserved cysteines. The cytoplasmic domain lacks an intrinsic tyrosine kinase domain. Nevertheless, it contains at least three “boxes” that can associate with cytoplasmic tyrosine kinases following gp130 homodimerization.51, 57 Three pathways are activated, in
14、cluding the JAK/STAT, Ras/Raf, and Src-family of kinases51, 58 Although IL-6 binding to gp130 has been described,59 it is generally reported that the 80 kDa IL-6 R is the actual IL-6 binding protein.6 Mouse gp130 has been cloned and found to be 77% identical to human gp130 at the aa level (72% ident
15、ity exists in the extracellular region).60 It possesses the same features as human gp130, and it will associate with human IL-6 and human IL-6 R to form a functional signaling complex.60 In the blood of normal individuals, soluble gp130 (sgp130) exists at concentrations approaching 400 ng/mL.61 Circ
16、umstances surrounding the generation of the soluble molecule are not clear. Two alternate splice forms lacking the transmembrane segment have been reported, one 624 aa62 and one 658 aa long.63 sgp130 functions as a down-modulator of IL-6 activity,61 something that is consistent with the observation that the transmembrane region of gp130 is necessary for full IL-6 signaling.64 Soluble gp130 will not bind to sIL-6 R unless IL-6 is present.61 Numerous cell types are res
