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Not all type I IFNs induce exactly the same range of responses, and the anti-viral:anti-proliferative activity ratio differs from one type I IFN to another. As all bind the same receptor, the molecular basis by which variation in biological activities is achieved, is poorly understood as yet.
IFN-g exhibits at best weak anti-viral and anti-proliferative activity. When co-administered with type I IFNs, however, it potentates these IFN-a/b activities. IFN-g is directly involved in regulating most aspects of the immune and inflammatory responses. It promotes activation, growth and differentiation of a wide variety of cell types involved in these physiological processes (Table 4.7).
IFN-g represents the main macrophage activating factor, thus enhancing macrophage-mediated effects, including:
Table 4.7. Cell types participating in the immune, inflammatory or other responses whose activation, growth and differentiation is promoted by IFN-g
• destruction of invading microorganisms;
• destruction of intracellular pathogens;
• tumour cell cytotoxicity;
• increased major histocompatibility complex (MHC) antigen expression, leading to enhanced
activation of lymphocytes via antigen presentation.
Binding of IFN-g to its surface receptor on polymorphonuclear neutrophils induces increased expression of the gene coding for a neutrophil cell surface protein capable of binding the Fc portion (i.e. the constant region: see also Box 10.2) of immunoglobulin (IgG). This greatly increases the phagocytotic and cytotoxic activities of these cells.
IFN-g also directly modulates the immune response by affecting growth, differentiation and function of both T and B lymphocytes. These effects are quite complex, and are often influenced by additional cytokines. IFN-g acts as a growth factor in an autocrine manner for some T cell sub-populations, while it is capable of suppressing growth of other T cell types. It appears to have an inhibitory effect on development of immature B lymphocyte populations but may support mature B cell survival. It can both upregulate and downregulate antibody production under various circumstances.
All IFNs promote increased surface expression of class I MHC antigens. Class II MHC antigen expression is stimulated mainly by IFN-g (MHC proteins are found on the surface of various cell types. They play an essential role in triggering an effective immune response, not only against foreign antigen but also against altered host cells). While many IFNs promote synergistic effects, some instances are known where two or more IFNs can oppose each other’s biological activities. IFN-aJ, for example, can inhibit the IFN-aA-mediated stimulation of NK cells.
The molecular basis by which IFNs promote their characteristic effects, particularly anti-viral activity, is understood at least in part. IFN stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These anti-viral gene products are generally enzymes, the most important of which are 2'-5' oligoadenylate synthetase (2, 5-An synthetase) and the eIF-2a protein kinase.
These intracellular enzymes remain in an inactive state after their initial induction. They are activated only when the cell comes under viral attack, and their activation can inhibit viral replication in that cell. The 2'-5' An, synthetase acts in concert with two additional enzymes — an endoribonuclease and a phosphodiesterase — to promote and regulate the anti-viral state (Figure 4.4).
Several active forms of the synthetase seem to be inducable in human cells; 40 kDa and 46 kDa variants have been identified which differ only in their carboxyl terminus ends. They are produced as a result of differential splicing of mRNA transcribed from a single gene found on chromosome 11. A larger 85-100 kDa form of the enzyme has been detected, which may represent a heterodimer composed of the 40 and 46 kDa variants.
The synthetase is activated by double-stranded RNA (dsRNA). Although not normally present in human cells, dsRNA is often associated with commencement of replication of certain viruses. The activated enzyme catalyses the synthesis of oligonucleotides of varying length in which the sole base is adenine (2'-5'An). This oligonucleotide differs from oligonucleotides present naturally in the cell in that the phosphodiester bonds present are 2'-5' bonds (Figure 4.5). The level of synthesis and average polymer length of the oligonucleotide products appear to depend upon the exact inducing IFN type, as well as the growth state of the cell.
THE CYTOKINES—THE INTERFERON FAMILY 205