Recombinant interferon-alpha (IFN-alpha) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-alpha paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. This review summarizes the history of the purification of human IFNs and the key aspects of our current state of knowledge of human IFN genes, proteins, and receptors. All the known IFNs and IFN-like cytokines are described [IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, IFN-omega, IFN-delta, IFN-tau, IFN-gamma, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29] as well as their receptors and signal transduction pathways. The biological activities and clinical applications of the proteins are discussed. An extensive section on the evolution of these molecules provides some new insights into the development of these proteins as major elements of innate immunity. The overall structure of the IFNs is put into perspective in relation to their receptors and functions.

The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.

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We identified a viral IL-10 homolog encoded by an ORF (UL111a) within the human cytomegalovirus (CMV) genome, which we designated cmvIL-10. cmvIL-10 can bind to the human IL-10 receptor and can compete with human IL-10 for binding sites, despite the fact that these two proteins are only 27% identical. cmvIL-10 requires both subunits of the IL-10 receptor complex to induce signal transduction events and biological activities. The structure of the cmvIL-10 gene is unique by itself. The gene retained two of four introns of the IL-10 gene, but the length of the introns was reduced. We demonstrated that cmvIL-10 is expressed in CMVinfected cells. Thus, expression of cmvIL-10 extends the range of counter measures developed by CMV to circumvent detection and destruction by the host immune system. I L-10 is a pleiotropic immunomodulatory cytokine produced by CD4 ϩ and CD8 ϩ T cells, monocytes͞macrophages, keratinocytes, and activated B cells (1). In addition, its expression is elevated in patients with a variety of peripheral blood or bone marrow-derived leukemias, certain B cell and T cell lymphomas and nasal natural killer cell lymphomas and other hematopoietic and solid tumors (1-5). Two mechanisms of IL-10 action can be used by tumors. IL-10 appears to act as an autocrine growth factor for B cell lymphomas. In addition, IL-10 selectively inhibits certain aspects of the cellular immune response. It blocks proinflammatory cytokine synthesis and suppresses the ability of macrophages to serve as antigen-presenting or costimulatory cells (6-8). Thus, IL-10 is a powerful anti-inflammatory agent and a potent immunosuppressor.Many viruses exploit the strategy of using homologs of cellular cytokines or cytokine receptors to shield virus-infected cells from immune defenses and enhance virus survival in the host. The presence of virus-encoded homologs of cellular proteins may be an indicator of the importance of these cellular components in immune mechanisms for combating this virus in vivo. A number of herpes viruses harbor homologs of IL-10. Epstein-Barr virus (EBV)-encoded IL-10 (ebvIL-10), the first viral homolog of IL-10 identified (9, 10), shares many but not all of the biological activities of cellular IL-10 and may play an important role in the host-virus interaction (1,11,12). In addition to EBV, another virus, the Orf poxvirus (OV), which can infect humans, has its own IL-10 homolog, ovIL-10 (13). Whether it is active on human cells remains to be shown. The exact in vivo roles of viral IL-10 homologs in the viral life cycle, in immune evasion, and͞or in helping virus-infected cells to survive immune surveillance remain to be defined.Human cytomegalovirus (CMV) is a widespread herpes virus that is able to persist for decades in its host. CMV is the major cause of a variety of life-threatening diseases in immunocompromised individuals, including transplant and AIDS patients, and is a leading cause of congenital birth defects (14). CMV is also associated with the development of atherosclerosis, restenosis after coronary...

We have identified a new mammalian protein arginine N-methyltransferase, PRMT5, formerly designated Janus kinase-binding protein 1, that can catalyze the formation of -N G -monomethylarginine and symmetric -N G ,N G -dimethylarginine in a variety of proteins. A hemagglutinin peptide-tagged PRMT5 complex purified from human HeLa cells catalyzes the S-adenosyl-L-[methyl-3 H]methionine-dependent in vitro methylation of myelin basic protein. When the radiolabeled myelin basic protein was acid-hydrolyzed to free amino acids, and the products were separated by high-resolution cation exchange chromatography, we were able to detect two tritiated species. One species co-migrated with a -N G -monomethylarginine standard, and the other cochromatographed with a symmetric -N G ,N G -dimethylarginine standard. Upon base treatment, this second species formed methylamine, a breakdown product characteristic of symmetric -N G ,N G -dimethylarginine. Further analysis of these two species by thin layer chromatography confirmed their identification as -N Gmonomethylarginine and symmetric -N G ,N G -dimethylarginine. The hemagglutinin-PRMT5 complex was also able to monomethylate and symmetrically dimethylate bovine histone H2A and a glutathione S-transferasefibrillarin (amino acids 1-148) fusion protein (glutathione S-transferase-GAR). A mutation introduced into the S-adenosyl-L-methionine-binding motif I of a myc-tagged PRMT5 construct in COS-1 cells led to a near complete loss of observed enzymatic activity. PRMT5 is the first example of a catalytic chain for a type II protein arginine N-methyltransferase that can result in the formation of symmetric dimethylarginine residues as observed previously in myelin basic protein, Sm small nuclear ribonucleoproteins, and other polypeptides.

Identification and functional characterization of a second chain of the interleukin-10 receptor complex cells, blocking their ability to secrete cytokines such as Serguei V.Kotenko, Christopher D.Krause, interferon-γ (IFN-γ) and IL-2 (Fiorentino et al., 1991;

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