Biomedical Engineering Reference
In-Depth Information
Table 8.5
Cell types which display an IFN-
γ
receptor on their surface
Haematopoietic cells
T-lymphocytes
B-lymphocytes
Macrophages
Polymorphonuclear leukocytes
Platelets
Somatic cells
Endothelial cells
Epithelial cells
Various tumour cells
8.2.5 The interferon receptors
The availability of large quantities of purifi ed interferons facilitates detailed study of the interferon
receptors. Binding studies using radiolabelled interferons can be undertaken, and photoaffi nity
cross-linking of labelled interferon to its receptor facilitates subsequent purifi cation of the lig-
and-receptor complex. Recombinant DNA technology also facilitated direct cloning of interferon
receptors. Binding studies using radiolabelled type I interferons reveals that they all compete for
binding to the same receptor, whereas purifi ed IFN-γ does not compete. Partial purifi cation of the
IFN-
receptor was undertaken by a number of means. One approach entailed covalent attach-
ment of radiolabelled IFN-α to the receptor using bifunctional cross-linking agents, followed by
purifi cation of the radioactive complex. An alternative approach utilized an immobilized IFN-
α
α
ligand for affi nity purifi cation. The receptor has also been cloned, and the gene is housed on hu-
man chromosome number 21.
Studies have actually revealed two type I interferon receptor polypeptides. Sequence data from
cloning studies place both in the class II cytokine receptor family. Both are transmembrane N-linked
glycoproteins. Studies using isolated forms of each show that one polypeptide (called the α/β recep-
tor) is capable of binding all type I interferons. The other one (the
receptor) is specifi c for IFN-
α-B (a specifi c member of the IFN-α family). Both receptors are present on most cell types.
The IFN-
αβ
receptor (the type II receptor) displays a more limited cellular distribution than that
of the type I receptors (Table 8.5). This receptor is a transmembrane glycoprotein of molecular
mass 50 kDa, which appears to function as a homodimer. The extracellular IFN-
γ
binding region
consists of approximately 200 amino acid residues folded into two homologous domains. Initiation
of signal transduction also requires the presence of a second transmembrane glycoprotein known
as AF-1 (accessory factor 1), which associates with the extracellular region of the receptor.
The intracellular events triggered upon binding of type I or II interferons to their respective
receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been
elucidated over the last few years. It has quickly become apparent that this pathway plays a promi-
nent role in mediating signal transduction, not only for interferon, but also of many cytokines.
γ
8.2.6 The JAK-STAT pathway
Cytokine receptors can be divided into two groups: those whose intracellular domains exhibit
intrinsic protein tyrosine kinase (PTK) activity and those whose intracellular domains are devoid
of such activity. Many of the latter group of receptors, however, activate intracellular soluble PTKs
upon ligand binding.
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