Interleukin-1 family

Dimarello CA (1994) The interleukin-1 family 10 years of discovery. FASEB J 8 1314-1325... 

Arend, W.P. (1991). Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J. Clin. Invest. 88, 1445-1451. 

Three members of the interleukin-1 family have been cloned (Dinarello 1996). All bind both types of receptors but only IL-la and IL-ip (encoded on chromosome 2) are agonists. The third is the interleukin 1 receptor antagonist protein (IRAP). All share 20-25 % amino acid homology. Mature IL-la and IL-ip have similar three-dimensional open barrel structures of P sheets. 

IL-2, also known as T-cell growth factor, represents the most studied member of the interleukin family. It was the first T-cell growth factor to be identified and it plays a central role in the immune response. It is produced exclusively by T-lymphocytes (especially T-helper cells), in response to activation by antigen and mitogens. 

The interleukin family of cytokines has been overviewed in Chapter 9, and a number of cytokines are known to influence haemopoiesis. The IL-3 receptor, for example, is found on a wide variety of progenitor haemopoietic cells, and appears to stimulate not only CFU-GEMM, but also the precursor cells of basophils, eosinophils and platelets. The role of IL-11, which also plays a role, was also discussed in Chapter 9. 

Interleukin family-R s Erythropoietin-R Low density lipoprotein-R Transferrin-R ... 

The third interleukin family is the IL-17 family. Interleukin-17 is a pro-inflamatory cytokine that is primarily secreted from T-lymphocytes and whose physiological significance is only just beginning to be determined [241, 242]. Increased urinary excretion of interleukin-17 has been found in nephrotic patients [243]. 

Inflammatory caspases (caspase-1, -4, -5,-11 and -12) constitute a subgroup of the caspase family. Caspase-1 is the best characterized member and is responsible for the proteolytic maturation and release of the pro-inflammatory cytokines pro-interleukin (IL)-1 (3 and pro-IL-18. Caspase-1 gets activated in inflammasome complexes upon cellular stress, cellular damage and infection. 

The interleukin-1 (EL-1) family of proteins currently comprises IL-1 a, IL-1 (3, and the IL-1 receptor antagonist (IL-1RA). The biological activities of EL-1 are shared by IL-1 a and IL-1 (3, whereas IL-1RA is a true receptor antagonist. IL-1 is a key player in acute and chronic inflammatory diseases. Whether IL-1 has a role in normal physiology is still unresolved. IL-1 can... 

Dong C Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev 2008 226 80-86. 

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.

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. 

The production of a female-influencing secretion from the chin gland of male Plethodontid salamander (P. jordani) points to a similar extension of function by the acquisition of female olfactory sensitivity to an intercellular signal protein. Female receptivity is enhanced by a male cytokine-like compound of the interleukin-6 family, in its released form. Rollman et al. (1999) note that pheromonal activity is a previously unrecognised function for cytokines. 

The term cytokine was first introduced in the mid 1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. The interferons and interleukins represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including lymphokines (cytokines such as IL-2 and IFN-y, produced by lymphocytes) and monokines (cytokines such as TNF-a, produced by monocytes). However, classification on the basis of producing cell types also proved inappropriate, as most cytokines are produced by a range of cell types (e.g. both lymphocytes and monocytes produce IFN-a). 

Some growth factors may be classified as cytokines (e.g. interleukins, TGF-P and CSFs). Others (e.g. IGFs) are not members of this family. Each growth factor has a mitogenic (promotes cell division) effect on a characteristic range of cells. Whereas some such factors affect only a few cell types, most stimulate growth of a wide range of cells. 

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modem techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin-1(3 (IL-1(3), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1 a, (3 (MIP-la,[3)J, MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family... 

Interleukins Interleukins are proteins produced mainly by leukocytes. There are many interleukins within this family (Table 4.4). Interleukins have a number of functions but are principally involved in mediating and directing immune cells to proliferate and differentiate. Each interleukin binds to a specific receptor and produces its response. 

Interleukin one of a family of proteins secreted by white blood cells that have a spectrum of regulatory effects on other white blood cells. 

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