The polypeptide hormone interleukin-1 (IL-1) is one of the key mediators of host's response to microbial invasion, inflammation, tissue injury, or immunological reactions. IL-1 is a prominent member of a group of polypeptide mediators now called cytokines.
The IL-1 gene family is composed of IL-1a, IL-1b, and IL-1Ra. Each member is first synthesized as a precursor protein; the precursors for IL-1 (prolL-1a and prolL-1b) each have a molecular mass of 31 kDa. The prolL-1a and mature 17 kDa lL-1a are both biologically active. In contrast, prolL-1b is relatively inactive and requires cleavage to a 17-kDa peptide for optimal biological activity. The IL-1Ra precursor has a leader sequence, is cleaved to its mature form, and is secreted like most proteins1.
IL-1 ligands (IL-1a and IL-1b, collectively referred to as IL-1) are pluripotent, proinflammatory cytokines. These two IL l’s share only small stretches of amino acid homology (26% in the case of human IL 1). Each IL 1 is coded by a separate gene, both genes are located on chromosome 2, and each gene contains seven exons. mRNA coding for IL-1b predominates over that coding for IL-1a and this prevalence of IL-1b has been observed in the proportion of the two IL 1 forms measured in the circulation and other body fluids. Both forms of IL 1 are unique in that they are initially translated as precursor polypeptides (31,000 kDa), and despite the fact that IL 1 is found in the extracellular compartment, neither form contains a signal cleavage sequence. The generation of the NH2 terminus of the mature peptide (17,500 kDa) and smaller peptides occurs by the action of senine proteases. Of particular interest is the a/b homologous region termed C-D, which is coded entirely by the sixth exon. It has been suggest that this region may contain the minimal recognition site for IL 1 receptors. Receptors for IL 1 equally recognize the b and a forms, both forms possess the same spectrum of biological properties, and molecular modeling studies reveal that the two IL l’s are composed of b - folded sheets2,3.
Mode of Action
IL 1 specifically binds to a variety of cells. Studies with T lymphocytes and fibroblasts suggest the existence of a single class of high-affinity receptor with a dissociation constant (KD) that varies from 5 to 50 pM with 100-4000 binding sites per cell. The high-affinity receptors are rapidly internalized and bind to nuclear structures, and responsiveness to IL 1 is down-regulated. The rapid down-regulation of IL 1 receptor is specific and may account, in part, for modulating IL1 effects in several cells4. In cells stimulated with IL1, cytosolic calcium increases, sodium/potassium ion fluxes occur, and protein kinase activity increases4.
Interleukin-1: Regulator of Neuroinflammation - Interleukins 1a and 1b (IL-1) are very potent signaling molecules that are expressed normally at low levels, but are induced rapidly in response to local or peripheral insults. IL-1 coordinates systemic host defense responses to pathogens and to injury within the central nervous system (CNS). Numerous reports have correlated the presence of IL-1 in the injured or diseased brain, and its effects on neurons and nonneuronal cells in the CNS, it has been recently shown that the importance of IL-1 signaling. Further it has been demonstrate that IL-1 is at or near the top of the hierarchical cytokine signaling cascade in the CNS that results in the activation of endogenous microglia and vascular endothelial cells to recruit peripheral leukocytes (i.e., neuroinflammation). The IL-1 system thus provides an attractive target for therapeutic intervention to ameliorate the destructive consequences of neuroinflammation5.
Role of interleukin-1 in stress responses - Stress responses have been characterized as central neurohormonal changes, as well as behavioral and physiological changes. Administration of IL-1 has been shown to induce effects comparable to stress-induced changes. IL-1 acts on the brain, especially the hypothalamus, to enhance release of monoamines, such as norepinephrine, dopamine, and serotonin, as well as secretion of corticotropin-releasing hormone (CRH). IL-1-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in vivo depends on secretion of CRH, an intact pituitary, and the ventral noradrenergic bundle that innervates the CRH-containing neurons in the paraventricular nucleus of the hypothalamus. Recent studies have shown that IL-1 is present within neurons in the brain, suggesting that IL-1 functions in neuronal transmission. It has been shown that IL-1 in the brain is involved in the stress response, and that stress-induced activation of monoamine release and the HPA axis were inhibited by IL-1 receptor antagonist (IL-1Ra) administration directly into the rat hypothalamus. IL-1Ra has been known to exert a blocking effect on IL-1 by competitively inhibiting the binding of IL-1 to IL-1 receptors6.
1. Dinarello CA (1994). The interleukin-1 family. 10 years of discovery. FASEBJ, 8(15):1314-25.
2. Auron PE, Warner SJ, Webb AC, Cannon JG, Bernheim HA, McAdam KJ, Rosenwasser LJ, LoPreste G, Mucci SF, Dinarello CA (1987). Studies on the molecular nature of human interleukin-1. J. Immunol, 138(5):1447-1456.
3. Dinarello C A (1988). Biology of interleukin 1. FASEBJ, 2: 108-115.
4. Mizel S B, Kilian P L, Lewis J C, Paganelli KA, Chizzonite RA (1987). The interleukin 1 receptor. Dynamics of interleukin 1 binding and internalization in T cells and fibroblasts. J. Immunol., 138: 2906-2912.
5. Basu A, Krady JK, Levison SW(2004). Interleukin-1: A Master Regulator of Neuroinflammation. Journal of Neuroscience Research, 78:151–156.
6. Shintani F, Nakaki T, Kanba S, Kato R, Asai M(1995). Role of interleukin-1 in stress responses - A putative neurotransmitter. Molecular Neurobiology, 10: 47-71.
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