Immunology Today, voL 7, No. 1 I, 1986
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Specific cell surface receptors for a number of cytokines, including interleukin 1 (IL-1), interleukin 2 (IL-2) and interleukin 3 (IL-3) were discussed in a variety of papers at the Congress. The problem of how the binding of a ligand to a surface receptor leads to an intracellular biochemical signal remains one of the most elusive issues in biology. IL-1 acts as a soluble mediator in inflammatory responses. A wide range of cell types, including lymphocytes, synovial cells, epithelial cells and fibroblasts are involved in such responses. The diverse range of biological effects of IL-1 raises the issue of whether it is a single molecular species or several different proteins. Several groups have reported that there are at least two polypeptides in man (S. Gillis, Seattle) and in mouse (C.A. Dinarello, Boston) which by virtue of their source, activated monocytes, and their biological effects, can be defined as IL-1. These have been termed IL-lc( and IL-113 and have been produced in recombinant form using various prokaryotic and eukaryotic expression systems. IL-113, produced by activated human monocytes, is a 17 500 Mr protein, and binds specifically to a variety of cells. Two unrelated cell lines, a murine T lymphoma line and murine fibroblast line, both bind ~251-1L-113 via similar plasma membrane receptor molecules. The T lymphoma cells possess 238 + 16 plasma membrane receptors per cell and bind [ 1 2 5 I]1L-113 with an affinity of 3.6 ± 0.9 x 109 M -~. The IL-1 receptor appears to be a 79 500 Mr protein as estimated by affinity crosslinking (S. Dower, Seattle). The fibroblasts possess 4.8 ± 0.5 × 103 IL-1 receptors per cell and bind [~251]1L-1[3 with an affinity of 2.6 ± 0.5 x 109 M -1, and the receptor is a similar size. Despite the similarity in the characteristics of the ligandreceptor system on the two different cell types, the biological responses of the two cell types to IL-113 occur at concentrations that differ by several orders of magnitude. Recombinant IL-I~ and IL-113 appear to bind to the same receptors. There appear to be only limited differences between the activities of IL-lct and IL-1[3 at the level of receptor binding, and almost no difference between natural and recombinant IL-113. The existence of two forms of IL-1 with limited primary sequence homology but which share
Cytokinesand their receptors JamesD. Watson biological activities is of major interest. Although the structural basis for these shared activities is undefined, and because these two polypeptides bind to the same receptor, it appears they possess similar receptor binding regions. Thus, it is likely these two molecules have tertiary structural features in common, even although this is not apparent from the sequences (Dower). The human and murine IL-2 receptor has now been cloned. It is an unusually small receptor molecule, consisting of a single polypeptide of 251 amino acids. Transfection of cells with the cDNA encoding this polypeptide has shown that its expression is sufficient to confer IL-2binding ability upon non-T-cell populations. A comparison of the human and murine receptor polypeptides has shown that the two most highly conserved regions are the 21 amino acid transmembrane domain and the 13 amino acid cytoplasmic domain. Presumably, these highly conserved regions are associated with important functional properties. Two forms of the IL-2 receptor are found on activated T cells and are distinguished by the affinity with which they bind IL-2. Approximately 5-10% of the receptors bind IL-2 with a Ka of >1 x 109 M -1, and remaining receptors with a Ka of
I 0
320
Specific cell surface receptors for a number of cytokines, including interleukin 1 (IL-1), interleukin 2 (IL-2) and interleukin 3 (IL-3) were discussed in a variety of papers at the Congress. The problem of how the binding of a ligand to a surface receptor leads to an intracellular biochemical signal remains one of the most elusive issues in biology. IL-1 acts as a soluble mediator in inflammatory responses. A wide range of cell types, including lymphocytes, synovial cells, epithelial cells and fibroblasts are involved in such responses. The diverse range of biological effects of IL-1 raises the issue of whether it is a single molecular species or several different proteins. Several groups have reported that there are at least two polypeptides in man (S. Gillis, Seattle) and in mouse (C.A. Dinarello, Boston) which by virtue of their source, activated monocytes, and their biological effects, can be defined as IL-1. These have been termed IL-lc( and IL-113 and have been produced in recombinant form using various prokaryotic and eukaryotic expression systems. IL-113, produced by activated human monocytes, is a 17 500 Mr protein, and binds specifically to a variety of cells. Two unrelated cell lines, a murine T lymphoma line and murine fibroblast line, both bind ~251-1L-113 via similar plasma membrane receptor molecules. The T lymphoma cells possess 238 + 16 plasma membrane receptors per cell and bind [ 1 2 5 I]1L-113 with an affinity of 3.6 ± 0.9 x 109 M -~. The IL-1 receptor appears to be a 79 500 Mr protein as estimated by affinity crosslinking (S. Dower, Seattle). The fibroblasts possess 4.8 ± 0.5 × 103 IL-1 receptors per cell and bind [~251]1L-1[3 with an affinity of 2.6 ± 0.5 x 109 M -1, and the receptor is a similar size. Despite the similarity in the characteristics of the ligandreceptor system on the two different cell types, the biological responses of the two cell types to IL-113 occur at concentrations that differ by several orders of magnitude. Recombinant IL-I~ and IL-113 appear to bind to the same receptors. There appear to be only limited differences between the activities of IL-lct and IL-1[3 at the level of receptor binding, and almost no difference between natural and recombinant IL-113. The existence of two forms of IL-1 with limited primary sequence homology but which share
Cytokinesand their receptors JamesD. Watson biological activities is of major interest. Although the structural basis for these shared activities is undefined, and because these two polypeptides bind to the same receptor, it appears they possess similar receptor binding regions. Thus, it is likely these two molecules have tertiary structural features in common, even although this is not apparent from the sequences (Dower). The human and murine IL-2 receptor has now been cloned. It is an unusually small receptor molecule, consisting of a single polypeptide of 251 amino acids. Transfection of cells with the cDNA encoding this polypeptide has shown that its expression is sufficient to confer IL-2binding ability upon non-T-cell populations. A comparison of the human and murine receptor polypeptides has shown that the two most highly conserved regions are the 21 amino acid transmembrane domain and the 13 amino acid cytoplasmic domain. Presumably, these highly conserved regions are associated with important functional properties. Two forms of the IL-2 receptor are found on activated T cells and are distinguished by the affinity with which they bind IL-2. Approximately 5-10% of the receptors bind IL-2 with a Ka of >1 x 109 M -1, and remaining receptors with a Ka of
