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Cytokines and their receptors
Cytokines
and their receptors Hilary
University
of California,
P. Benton Davis, California,
USA
Cytokines act via receptor-mediated pathways to influence the regulation of both immune and non-immune cells. This review will discuss some of the most important developments over the past year which have contributed to the elucidation of the mechanisms of cell activation by these molecules.
Current
Opinion
in Cell Biology
Introduction The term cytokine is used to describe the large number of proteins which mediate significant roles in growth, differentiation and tissue damage via cell surface receptors. Growth factors are often included among this class of molecules, although the original definition was limited to the family of humoral factors, including lymphokines, monokines, interleukins and interferons, known to reg ulate cells of hematopoietic lineage. In this review, examples of cytokines will be limited to this latter class of immune and hematopoietic regulatory molecules. It must be emphasized, however, that much of the evidence that has accumulated demonstrates that these molecules also have important physiological and pathological significance for cells of most other lineages, including epithelial and connective tissue cells. For instance, interferon (IFN)-y enhances the expression of MHC class II antigens, enabling a number of non-Immune cell-types to present antigens [ 1 ] . Most cell types are capable of syrthesizing and expressing interleukin (IL)-1 cell surface receptors. IL-1 mediates a wide range of inflammatory and degradative processes [2], and has been implicated in a number of pathological processes such as rheumatoid arthritis. Tumor necrosis factor (TNF)-a( mimics many of the actions of IL-l, but also has unique biological activities [4]. Colony-stimulating factor (CSF), until recently thought to be restricted to immune and hematopoietic functions, is now reported possibly to perform a wider range of biological activities [ 51. Although growth factors will not be used directly as examples in this review, it is often logical to class them together with cytokines such as the interleukins and interferons, because their modes of action overlap significantly. Hence, much of the discussion about cell surface receptor activation by cytokines will be equally applicable to many growth factors. This review is not intended to cover our knowledge of cytokine functions and mechanism of action extensively. Instead, I will build on the information presented last year in this journal [3] by providing an update on progress in cloning of cytokines and cytokine receptor genes. The structural infomration this process supplies is essential
1991, 3~171-175
to obtain the molecular probes required to elucidate the mechanisms of action of the encoded proteins. Current approaches to understanding the signal transduction pathways activated by cytokine-cytokine receptor interaction will be discussed. Cytokine receptor new members
families:
identification
of
For the newcomer to the field, the cytokine family can seem overwhelmingly large because of the multiple terminology used for identical factors originally isolated from different sources. A recent appendix has been produced that provides a good cross-reference to the older terminology [ 61. Many cytokine receptors have now been cloned and sequenced, and members of receptor ‘families’ sharing common structural features can be identified [3]. The T-cell IL-l receptor (71 and the CSF-1 receptor [8,9] were identified as members of the immunoglobulin superfamily but, perhaps surprisingly, no other cytokine receptor genes cloned to date show any similarity to this family. The largest and most rapidly expanding receptor family is the cytokine or growth factor receptor family which includes the receptors for growth hormone and prolactin as well as a number of cytokine receptors (Fig. 1). In the past year, genes encoding a murine granulocyte-CSF receptor [lo*] and an IL-3 receptor [ll.] have been cloned, and both have been shown to possess sequence similarity to this class of receptors. Interferons are class&d together because of their antiviral, anti-proliferative and immunoregulatory activities. IFN-a and IFN-P crossreact with a common receptor that has yet to be cloned, but IFN-y acts via a distinct receptor [ 121. Continued attention has been paid to the cloning of the murine IFN-y receptor gene [ 13*-15.1, despite the earlier cloning and sequencing of the human receptor gene [ 161, in an attempt to elucidate the reasons for the marked species speciticity of this receptor [3]. Comparison of the predicted primary amino acid sequence of
Abbreviations CSF-colony-stimulating
factor;
IFN-interferon;
IL-interleukin;
@ Current
Biology
IL-lra-IL-1
receptor antagonist; TNF-tumor
Ltd ISSN 0955-0674
necrosis factor.
172
Cell regulation
. Cytokine/growth factor receptor family
lmmunoglobulin superfamily
NGF receptor family
Interferon-y receptor
Extracellular
!I NGFr
TNFr
IL-3r Intracellular CSF-1 r
the human and murine receptors shows that a number of gaps must be introduced in order to align the cytoplas mic domains of the two molecules [ l3*]. It may be that the apparent homology quoted of over 50% is misleading, particularly with respect to the intracellular domains. Further experiments are required to elucidate the nature of the chromosome 21-encoded factor [ 171 that appears to be necessary for signal transduction via the human receptor. The cloned IFN-y receptor does not show sequence homology to any other cloned cytokine or growth factor. Recent cloning of a human TNF receptor [ 18*=-20*=] has conlirmed earlier receptor binding studies demonstrating that ‘INF-u and ‘T’NF+l compete for the same cell surface binding sites [ 211. This competition occurs even though substantial sequence tierences occur in all but the final two exons of each gene [22]. Similarly, the cloned IL-1 receptor [7] is capable of binding both IL-la and IL-lp, despite limlted sequence homology (less than 30%) between the two proteins. Receptor binding studies with both TNF-a [23*] and IL-1 suggest the presence of more than one receptor subtype for each cytokine. The 80 kD IL-1 receptor isolated from the mouse thymoma cell line,
Fig. 1. A schematic
diagram showing structural relationship between some recently cloned cytokine receptors. 0 represent cysteine-rich domains. Members of the cytokine/growth factor family contain conserved motifs containing four cysteine residues and a second motif, H, representing the WS-WS box. Both these motifs are repeated in the interleukin (IL)-3 receptor extracellular domain. The IL-1 receptor and colony-stimulating factor KSFJ-1 receptor have three and five cysteine-rich immunoglobulin-like domains, respectively, and the CSF-1 receptor contains a tyrosine kinase domain (El). The tumor necrosis factor fTNF) receptor shares four repeated cysteine-rich domains with members of the nerve growth factor (NCF) receptor family and there are still no cloned receptors which show homology with the interferon (IFNPy receptor. The receptors are drawn approximately to scale. GM, granulocyte macrophage; r, receptor.
EL4, is larger than the 66kD IL-I receptors expressed in the B lymphoid cell line 7OZ/3 [24-l or on macrophages and bone marrow cells [25*]. Moreover, investigation of a number of B-cell lines suggests the presence of multiple IL-1 binding sites with differing affinities for IL-lu and IL-1 p [ 26.1. It seems likely, therefore, that in the near fu mre even more specific receptors for TNF and IL-1 will be cloned. The TNF receptor gene product characterized at present does not share sequence homology with members of the cytokine/growth factor receptor family, or with members of the immunoglobulin superfamily. The presence of a number of cysteine-rich repeats in the extracellular domain of the TNF receptor has led to comparison with the nerve growth factor receptor and other cysteine-rich receptors [ 18**-20**]. The classilication of cytokine receptors within these families, while implicating common ancestral genes for the various family members, has not shed light on their mechanisms of action. For example, despite common immunoglobulinlike extracellular domains, the intracellular domain of the cloned IL-1 receptor [7] shares no homology with the CSF-1 receptor [8], and does not possess a tyrosine ki-
Cytokines
and their
receptors Benton
nase domain. Given a substantial overlap in their biological responses it is almost surprising to learn that the TNF receptor discussed here [ 18**-20**] shares no homology with the IL-1 receptor.
and cellular events triggered later in the signalling cascade. Although it is essential to identify cytokine receptorcoupled events experimentally, their role in mediating cytokine actions must be critically evaluated.
Cytokine
Cytokine-mediated phosphorylation
inhibitors
Perhaps one of the most exciting advances in cytokine research is our knowledge of specific, possibly physiological, cytokine antagonists of potential therapeutic use. The cytokine network is clearly under complex control, and the production and secretion of cytokines appears to be regulated at the transcriptional, translational and post-translational level. It now seems that the presence of endogenous cytokine receptor antagonists may provide yet another means of influencing the final response to some cytokines. Over the last few years, there have been a number of reports of inhibitors of IL-1 activity, most commonly derived from human urine but also from serum and a variety of ceU lines (for a review see [ 271). More recently, a gene encoding an IL-1 receptor antagonist (IL-lra) has been cloned, both from human monocytes [28**] and a human myelomonocytic ceU line, U937 [ 29**]. The amino acid sequence predicts one N-linked glycosylation site, consistent with the puriiication of several glycosylated forms of the protein [ 29.0, 30**]. The IL-lra is a pure receptor antagonist, inhibiting many of the biological actions of IL-1 [ 29=*,31=,32*], including the ability to suppress the severity of endotoxin shock [33**]. This antagonist is speciiic for the T-cell IL-l receptor located on EL4 cells [30**] but has no apparent effect on the putative B-cell IL-l receptor [ 29”,30**,32*]. Two specific TNF inhibitors or binding proteins have been isolated from human urine [ 34-36,37**]. Polyclonal antisera have been raised to each of these proteins, which bind differentially to receptors on a variety of ceU lines [37**]. This has led to the hypothesis that TNF-binding proteins may be structurally related to different TNFreceptor subtypes [23*,37**], and that soluble forms of cytokine receptors may serve to downregulate their respective ceU surface-bound receptors. This suggestion is supported further by the finding that the recently cloned TNF receptor gene [18**-20a*] encodes a protein expressed in a soluble form with structural similarity to the purified TNF-binding protein [34-361. It will be important to determine whether soluble forms of other cytokine receptors, such as the IL-4 and IL-~ receptors, can function in the same way. Cytokine
receptors
and signal
transduction
The elucidation of the mechanisms by which cytokines trigger speciUc intracellular events by binding to cell surface receptors remains a major challenge if the biological actions of cytokines are to be understood. Because the cellular responses that follow l&and binding to cytokine receptors are profoundly influenced by a wide range of other cellular mediators, it is often diIUcult to differentiate between speciIic cytokine receptor-mediated events,
regulation
of
Protein phosphorylation is now recognized as the final common pathway in intracellular communication and ceU regulation. It is expected, therefore, that the activation of cytokine receptors will regulate the phosphorylation state of cellular proteins, either directly or indirectly, As with many of the growth factor receptors, there is substantial evidence for the involvement of tyrosine phosphorylation in cytokine signal transduction, particularly for the cytokines that initiate a proliferative response. Some cytokine receptors, such as the CSF-1receptor, possess an intracellular tyrosine kinase domain, whereas others have portions that can act as a substrate for a nonreceptor tyrosine kinase. A number of reports in the past year demonstrate that stimulation of cells with IL-2 results in tyrosine phosphorylation of a variety of proteins [38*,39’,40,41]. The IL2 receptor consists of a dimer of a 55kD and a 75kD chain. The use of ceU lines expressing only one or other of these chains shows that it is the 75kD chain which is a substrate for tyrosine kinase activity [38*,39-l. This is consistent with the demonstration that an intracellular portion of this chain is essential for the stimulation of IL2-induced proliferation [42]. Further use of multiple ceU lines has provided evidence for both tyrosine and serine phosphorylation in response to IL-2, although only a subset of phosphorylated proteins were found to be substrates in all ceU lines tested [43]. Moreover, the HL2 helper T-cell line proliferated in response to both IL-2 and IL-4, in the absence of induced protein tyrosine phosphorylation, demonstrating that tyrosine kinase activity is not necessarily a prerequisite for cytokine-induced proliferation. Stimulation of protein phosphorylation has also been reported in response to receptor activation by granulocyteCSF, granulocyte/macrophage-CSF, TNF-a( and IFN-y [ 441. Both IL-1 and TNF-a cause increased phosphorylation of a small heat-shock protein and the epidermal growth factor receptor [45,46], and a novel kinase specific for IL-1 and TNF has been proposed [46]. The recently cloned IL-~ receptor gene does not encode a tyrosine kinase domain [ 11.1, but there is much evidence suggesting the IL-3 receptor may act as a substrate for a tyrosine kinase. Protein-protein interactions in cytokine-dependent cell activation The current enthusiasm for second messengers must be tempered with an awareness that some signalling cascades may involve l&and-triggered protein-protein interactions that do not require covalent modification. This
173
174
Cell regul&ion
possibility has been eloquentty discussed k~ another recent review [47**]. The cytokine and growth factor receptors each transcriptionally regulate a unique, but often overlapping, set of genes. The novelty of these generegylatory receptors may require the invocation of a new and hitherto neglected possibility; that these mediators do not ins&e covalent modification or second messengers in their signal transduction pathways.
Sequence homology between the murine granulocyte-CSF receptor and members of the cytokine/growth factor receptor family is shown. 11. .
ITOH N, YONEHARAS, !XHREURSJ, GORMANDM, MARUYAMAK, I~HII A, Ym 1, ARU K, MN~ A: Cloning of an Interleukin 3 Receptor Gene: a Member of a Distinct Receptor Gene Family. Science 1990, 247324-327. An IL-3 receptor is identified as a member of the cytokine/growth factor receptor family. 12.
PE~TKAS, IANGERJA, ZOON KC, SAMUELCE: Interferons Actions. Annu Rev Biocbem 1987, 56:727-777.
and
Their
Concluding
Although the molecular genetics defining the receptors for identikd cytokines is approaching completion, their pathways of action remain elusive. Several recent advances, including the identilication of specilic cytokine inhibitors, serve to emphasize the complexity of regulation of these molecules which are clearly important not only for cells of immune and hematopoetic cell lineage but also for a number of other cell systems. References
and recommended
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Papers of special interest, published within the annual period of review, have been highlighted as: . of interest .. of outstanding interest
COFANO F. MOORE SK, TANAKA S, YUHKI N, Lwtx~=o S, APPEIM E: AfBnity Puri&ation, Peptide Analysis and cDNA Sequence of the Mouse Interferon y Receptor. / Biol cbem 1990 265:4064-4071. The sequence of the same IFN-y cDNA clone as reported in [ 13.1 and [14*]. 16.
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10. .
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remirks
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SCHAU q, LEWIS M, KOUER KJ, LEE A, RICE GC, WONG GHW, GATANAGAT, GRANGERGA, I&NR. R, Rw H, KOHR WJ, GOEDDEL DV: Molecular Cloning and Expression of a Receptor for Human Tumor Necrosis Factor. cell 1990, 61:361-370. Molecular cloning of a receptor for human TNF with homology to members of the nerve growth factor receptor family, and comparable &nity for TNF-a and TNF-p. Expression in a variety of human tissues and cell lines is demonstrated. LYNCHER H, PAN Y-C E, IAHM H-W, GE~V~ZR, BROCKHAUSM, TABUCHIH, IESSLAUERW: Molecular Cloning and Expression of the Human 55kD Tumor Necrosis Factor Receptor. Cell 1990, 61:351-359. Molecular cloning of the same TNF receptor as [ 18**]. No expression is seen in Raji cells. Sequence similarity to an isolated TNF-binding protein, thought to be generated by proteotydc processing of the receptor molecule, is shown.
19. ..
GRAY PW, Bm K, Cnzwr~~ D, TURNERM, FELDMANNM: Cloning of Human Tumor Necrosis Factor (TNT) Receptor cDNA and Expression of Recombinant Soluble TNF-binding Protein. Pra: Nat1 Acad Sci USA 1990, 8773-7384. Cloning of the same human TNF receptor as in [ 18*e] and [ 19**], and demonstration that expression of the extracellular domain in COS cells results in secretion of a soluble portion of the receptor, similar to the TNF-binding protein. 20.
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H-P,
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REMY R, BR~CKHAUS
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25.
CHQZXITE KP. KAIXA
R, TRUtIT T, KU&N PI STERN AS, Nurw.s P, PARKER KI, CHUA AO, LUGG DK, GUBLER IJ: tie High-
Affinity Interleukin 1 Receptors Represent Separate Gene Products. Proc Nat1 Acud Sci USA 1989, &802+8033. Immunoprecipitation, and Sl nuclease protection assays using probes specific for the cloned T-cell receptor, suggest the existence of multiple IL-1 receptors representing independent gene products. S, DOWERSK: Heterogeneity in Inter. leukin (IL)-1 Receptors Expressed on Human B CeU Lines. J Biol than 1990, 2659943-9951. Comparison of IL-1 binding in a number of B cell lines implies the presence of multiple B cell IL-1 receptors. 26.
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CH, WILCOX CJ. AREND WP, JOSUN FG, DI~PPS DJ, PI ARMES LG, SUMMER A, EISENBERG SP, THOMPSON
RC: Interleukin-1 Receptor Antagonist Activity of a Human Interleukin-1 Inhibitor. Nature 1990, 343336-340. PurUicatIon of three interleukin-I inhibitors from human monocytes that are differen&@ gIycosyIated forms of the receptor antagonist described Bi. ol0gica.I Properties of Recombinant Human Monocytederived Interleukin-1 Receptor Antagonist. J Clin Invest 1990, 851694-1697. Demonstration that the cloned IL-lra is a frue receptor antagonist in several physiologicalIy and pathologically relevant systems, including lymphocytes. synovial cells and chondmcytes. AREND
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K, BJORK P, BERGENFELDT
M, HAGEMANN
R, THOMPSON
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..
HP Benton, Department of Zoology, Storer Hall, University of Cahfornia, Davis, Callfomla 95616, USA
175
and their receptors Hilary
University
of California,
P. Benton Davis, California,
USA
Cytokines act via receptor-mediated pathways to influence the regulation of both immune and non-immune cells. This review will discuss some of the most important developments over the past year which have contributed to the elucidation of the mechanisms of cell activation by these molecules.
Current
Opinion
in Cell Biology
Introduction The term cytokine is used to describe the large number of proteins which mediate significant roles in growth, differentiation and tissue damage via cell surface receptors. Growth factors are often included among this class of molecules, although the original definition was limited to the family of humoral factors, including lymphokines, monokines, interleukins and interferons, known to reg ulate cells of hematopoietic lineage. In this review, examples of cytokines will be limited to this latter class of immune and hematopoietic regulatory molecules. It must be emphasized, however, that much of the evidence that has accumulated demonstrates that these molecules also have important physiological and pathological significance for cells of most other lineages, including epithelial and connective tissue cells. For instance, interferon (IFN)-y enhances the expression of MHC class II antigens, enabling a number of non-Immune cell-types to present antigens [ 1 ] . Most cell types are capable of syrthesizing and expressing interleukin (IL)-1 cell surface receptors. IL-1 mediates a wide range of inflammatory and degradative processes [2], and has been implicated in a number of pathological processes such as rheumatoid arthritis. Tumor necrosis factor (TNF)-a( mimics many of the actions of IL-l, but also has unique biological activities [4]. Colony-stimulating factor (CSF), until recently thought to be restricted to immune and hematopoietic functions, is now reported possibly to perform a wider range of biological activities [ 51. Although growth factors will not be used directly as examples in this review, it is often logical to class them together with cytokines such as the interleukins and interferons, because their modes of action overlap significantly. Hence, much of the discussion about cell surface receptor activation by cytokines will be equally applicable to many growth factors. This review is not intended to cover our knowledge of cytokine functions and mechanism of action extensively. Instead, I will build on the information presented last year in this journal [3] by providing an update on progress in cloning of cytokines and cytokine receptor genes. The structural infomration this process supplies is essential
1991, 3~171-175
to obtain the molecular probes required to elucidate the mechanisms of action of the encoded proteins. Current approaches to understanding the signal transduction pathways activated by cytokine-cytokine receptor interaction will be discussed. Cytokine receptor new members
families:
identification
of
For the newcomer to the field, the cytokine family can seem overwhelmingly large because of the multiple terminology used for identical factors originally isolated from different sources. A recent appendix has been produced that provides a good cross-reference to the older terminology [ 61. Many cytokine receptors have now been cloned and sequenced, and members of receptor ‘families’ sharing common structural features can be identified [3]. The T-cell IL-l receptor (71 and the CSF-1 receptor [8,9] were identified as members of the immunoglobulin superfamily but, perhaps surprisingly, no other cytokine receptor genes cloned to date show any similarity to this family. The largest and most rapidly expanding receptor family is the cytokine or growth factor receptor family which includes the receptors for growth hormone and prolactin as well as a number of cytokine receptors (Fig. 1). In the past year, genes encoding a murine granulocyte-CSF receptor [lo*] and an IL-3 receptor [ll.] have been cloned, and both have been shown to possess sequence similarity to this class of receptors. Interferons are class&d together because of their antiviral, anti-proliferative and immunoregulatory activities. IFN-a and IFN-P crossreact with a common receptor that has yet to be cloned, but IFN-y acts via a distinct receptor [ 121. Continued attention has been paid to the cloning of the murine IFN-y receptor gene [ 13*-15.1, despite the earlier cloning and sequencing of the human receptor gene [ 161, in an attempt to elucidate the reasons for the marked species speciticity of this receptor [3]. Comparison of the predicted primary amino acid sequence of
Abbreviations CSF-colony-stimulating
factor;
IFN-interferon;
IL-interleukin;
@ Current
Biology
IL-lra-IL-1
receptor antagonist; TNF-tumor
Ltd ISSN 0955-0674
necrosis factor.
172
Cell regulation
. Cytokine/growth factor receptor family
lmmunoglobulin superfamily
NGF receptor family
Interferon-y receptor
Extracellular
!I NGFr
TNFr
IL-3r Intracellular CSF-1 r
the human and murine receptors shows that a number of gaps must be introduced in order to align the cytoplas mic domains of the two molecules [ l3*]. It may be that the apparent homology quoted of over 50% is misleading, particularly with respect to the intracellular domains. Further experiments are required to elucidate the nature of the chromosome 21-encoded factor [ 171 that appears to be necessary for signal transduction via the human receptor. The cloned IFN-y receptor does not show sequence homology to any other cloned cytokine or growth factor. Recent cloning of a human TNF receptor [ 18*=-20*=] has conlirmed earlier receptor binding studies demonstrating that ‘INF-u and ‘T’NF+l compete for the same cell surface binding sites [ 211. This competition occurs even though substantial sequence tierences occur in all but the final two exons of each gene [22]. Similarly, the cloned IL-1 receptor [7] is capable of binding both IL-la and IL-lp, despite limlted sequence homology (less than 30%) between the two proteins. Receptor binding studies with both TNF-a [23*] and IL-1 suggest the presence of more than one receptor subtype for each cytokine. The 80 kD IL-1 receptor isolated from the mouse thymoma cell line,
Fig. 1. A schematic
diagram showing structural relationship between some recently cloned cytokine receptors. 0 represent cysteine-rich domains. Members of the cytokine/growth factor family contain conserved motifs containing four cysteine residues and a second motif, H, representing the WS-WS box. Both these motifs are repeated in the interleukin (IL)-3 receptor extracellular domain. The IL-1 receptor and colony-stimulating factor KSFJ-1 receptor have three and five cysteine-rich immunoglobulin-like domains, respectively, and the CSF-1 receptor contains a tyrosine kinase domain (El). The tumor necrosis factor fTNF) receptor shares four repeated cysteine-rich domains with members of the nerve growth factor (NCF) receptor family and there are still no cloned receptors which show homology with the interferon (IFNPy receptor. The receptors are drawn approximately to scale. GM, granulocyte macrophage; r, receptor.
EL4, is larger than the 66kD IL-I receptors expressed in the B lymphoid cell line 7OZ/3 [24-l or on macrophages and bone marrow cells [25*]. Moreover, investigation of a number of B-cell lines suggests the presence of multiple IL-1 binding sites with differing affinities for IL-lu and IL-1 p [ 26.1. It seems likely, therefore, that in the near fu mre even more specific receptors for TNF and IL-1 will be cloned. The TNF receptor gene product characterized at present does not share sequence homology with members of the cytokine/growth factor receptor family, or with members of the immunoglobulin superfamily. The presence of a number of cysteine-rich repeats in the extracellular domain of the TNF receptor has led to comparison with the nerve growth factor receptor and other cysteine-rich receptors [ 18**-20**]. The classilication of cytokine receptors within these families, while implicating common ancestral genes for the various family members, has not shed light on their mechanisms of action. For example, despite common immunoglobulinlike extracellular domains, the intracellular domain of the cloned IL-1 receptor [7] shares no homology with the CSF-1 receptor [8], and does not possess a tyrosine ki-
Cytokines
and their
receptors Benton
nase domain. Given a substantial overlap in their biological responses it is almost surprising to learn that the TNF receptor discussed here [ 18**-20**] shares no homology with the IL-1 receptor.
and cellular events triggered later in the signalling cascade. Although it is essential to identify cytokine receptorcoupled events experimentally, their role in mediating cytokine actions must be critically evaluated.
Cytokine
Cytokine-mediated phosphorylation
inhibitors
Perhaps one of the most exciting advances in cytokine research is our knowledge of specific, possibly physiological, cytokine antagonists of potential therapeutic use. The cytokine network is clearly under complex control, and the production and secretion of cytokines appears to be regulated at the transcriptional, translational and post-translational level. It now seems that the presence of endogenous cytokine receptor antagonists may provide yet another means of influencing the final response to some cytokines. Over the last few years, there have been a number of reports of inhibitors of IL-1 activity, most commonly derived from human urine but also from serum and a variety of ceU lines (for a review see [ 271). More recently, a gene encoding an IL-1 receptor antagonist (IL-lra) has been cloned, both from human monocytes [28**] and a human myelomonocytic ceU line, U937 [ 29**]. The amino acid sequence predicts one N-linked glycosylation site, consistent with the puriiication of several glycosylated forms of the protein [ 29.0, 30**]. The IL-lra is a pure receptor antagonist, inhibiting many of the biological actions of IL-1 [ 29=*,31=,32*], including the ability to suppress the severity of endotoxin shock [33**]. This antagonist is speciiic for the T-cell IL-l receptor located on EL4 cells [30**] but has no apparent effect on the putative B-cell IL-l receptor [ 29”,30**,32*]. Two specific TNF inhibitors or binding proteins have been isolated from human urine [ 34-36,37**]. Polyclonal antisera have been raised to each of these proteins, which bind differentially to receptors on a variety of ceU lines [37**]. This has led to the hypothesis that TNF-binding proteins may be structurally related to different TNFreceptor subtypes [23*,37**], and that soluble forms of cytokine receptors may serve to downregulate their respective ceU surface-bound receptors. This suggestion is supported further by the finding that the recently cloned TNF receptor gene [18**-20a*] encodes a protein expressed in a soluble form with structural similarity to the purified TNF-binding protein [34-361. It will be important to determine whether soluble forms of other cytokine receptors, such as the IL-4 and IL-~ receptors, can function in the same way. Cytokine
receptors
and signal
transduction
The elucidation of the mechanisms by which cytokines trigger speciUc intracellular events by binding to cell surface receptors remains a major challenge if the biological actions of cytokines are to be understood. Because the cellular responses that follow l&and binding to cytokine receptors are profoundly influenced by a wide range of other cellular mediators, it is often diIUcult to differentiate between speciIic cytokine receptor-mediated events,
regulation
of
Protein phosphorylation is now recognized as the final common pathway in intracellular communication and ceU regulation. It is expected, therefore, that the activation of cytokine receptors will regulate the phosphorylation state of cellular proteins, either directly or indirectly, As with many of the growth factor receptors, there is substantial evidence for the involvement of tyrosine phosphorylation in cytokine signal transduction, particularly for the cytokines that initiate a proliferative response. Some cytokine receptors, such as the CSF-1receptor, possess an intracellular tyrosine kinase domain, whereas others have portions that can act as a substrate for a nonreceptor tyrosine kinase. A number of reports in the past year demonstrate that stimulation of cells with IL-2 results in tyrosine phosphorylation of a variety of proteins [38*,39’,40,41]. The IL2 receptor consists of a dimer of a 55kD and a 75kD chain. The use of ceU lines expressing only one or other of these chains shows that it is the 75kD chain which is a substrate for tyrosine kinase activity [38*,39-l. This is consistent with the demonstration that an intracellular portion of this chain is essential for the stimulation of IL2-induced proliferation [42]. Further use of multiple ceU lines has provided evidence for both tyrosine and serine phosphorylation in response to IL-2, although only a subset of phosphorylated proteins were found to be substrates in all ceU lines tested [43]. Moreover, the HL2 helper T-cell line proliferated in response to both IL-2 and IL-4, in the absence of induced protein tyrosine phosphorylation, demonstrating that tyrosine kinase activity is not necessarily a prerequisite for cytokine-induced proliferation. Stimulation of protein phosphorylation has also been reported in response to receptor activation by granulocyteCSF, granulocyte/macrophage-CSF, TNF-a( and IFN-y [ 441. Both IL-1 and TNF-a cause increased phosphorylation of a small heat-shock protein and the epidermal growth factor receptor [45,46], and a novel kinase specific for IL-1 and TNF has been proposed [46]. The recently cloned IL-~ receptor gene does not encode a tyrosine kinase domain [ 11.1, but there is much evidence suggesting the IL-3 receptor may act as a substrate for a tyrosine kinase. Protein-protein interactions in cytokine-dependent cell activation The current enthusiasm for second messengers must be tempered with an awareness that some signalling cascades may involve l&and-triggered protein-protein interactions that do not require covalent modification. This
173
174
Cell regul&ion
possibility has been eloquentty discussed k~ another recent review [47**]. The cytokine and growth factor receptors each transcriptionally regulate a unique, but often overlapping, set of genes. The novelty of these generegylatory receptors may require the invocation of a new and hitherto neglected possibility; that these mediators do not ins&e covalent modification or second messengers in their signal transduction pathways.
Sequence homology between the murine granulocyte-CSF receptor and members of the cytokine/growth factor receptor family is shown. 11. .
ITOH N, YONEHARAS, !XHREURSJ, GORMANDM, MARUYAMAK, I~HII A, Ym 1, ARU K, MN~ A: Cloning of an Interleukin 3 Receptor Gene: a Member of a Distinct Receptor Gene Family. Science 1990, 247324-327. An IL-3 receptor is identified as a member of the cytokine/growth factor receptor family. 12.
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and
Their
Concluding
Although the molecular genetics defining the receptors for identikd cytokines is approaching completion, their pathways of action remain elusive. Several recent advances, including the identilication of specilic cytokine inhibitors, serve to emphasize the complexity of regulation of these molecules which are clearly important not only for cells of immune and hematopoetic cell lineage but also for a number of other cell systems. References
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HP Benton, Department of Zoology, Storer Hall, University of Cahfornia, Davis, Callfomla 95616, USA
175