IL-3 and GM-CSF induce tyrosine phosphorylation of the protein tyrosine phosphatase, SH-PTP2, leading to its activation and association with GRB2 and PI3′-kinase

Today, systemic pharmacotherapy is an integral part of modern dermatotherapy.149, 210, 233, 240 The discovery of interferons by Isaacs and Lindemann in 1957 and the supply of molecular genetically defined, purified material at the beginning of the 1980s was the basis for the clinical use of the so called “biological response modifier.”117 Because of the antiviral, antiproliferative, and immunomodulating effects of the three major interferon types α, β, and γ, these cytokines were regarded as therapy for various viral and tumorous diseases. This rather irrational approach has been replaced by a rational use of these biological substances for definitive indications, similar to other drugs. This procedure showed clearly that these substances used in nanomolary concentrations trigger a pharmacodynamic effect that cannot be compared to conventional drugs.Meanwhile, it could be shown that at certain doses and at respective therapy intervals (but mainly in combination with other drugs), cytokines, especially interferons, open new therapeutic paths. In the last few years, other cytokines were discovered and their protein structure characterized: the interleukin family (IL 1–18), tumor necrosis factor (TNF), and the colony stimulating factors (GCSF, GMCSF); and the growth factors, for instance epidermal growth factor (EGF), transforming growth factor α (TGF α and β), fibroblast growth factor (FGF), nerve growth factor (NGF), insulin like growth factor (IGF), and platelet derived growth factor (PDGF). In a complex cytokine net these proteins play a central role in transmitting signals in immunologic reactions, in inflammation, in cell differentiation, and in cell and tumor growth.20, 28, 36, 62, 148, 149 As these factors are supplied as recombinant molecules and as more knowledge regarding their complex biological characteristics is gained, they will be used in future in experimental therapy protocols for tumorous diseases as well as inflammatory diseases.80, 138, 174Interferons are a protein family that is synthesized into leukocytes, fibroblasts, and T-lymphocytes because of viral infections, double funicular RNA antigens, or mitogens. Interferons were initially classified by their source as leukocyte, fibroblast, or immune interferon. Leukocyte and fibroblast interferon together were also designated type 1 interferons and immune interferon as type 2 interferon. The current nomenclature for interferons was determined by sequence analysis of the interferon genes (Table 1).109, 137, 250 According to this classification, there are four varieties of interferons: IFN-α, IFN-ω, IFN-β, and IFN-γ. In humans, there are at least 18 nonallelic IFN-α genes, four of which are pseudogenes, and at least six nonallelic IFN-ω interferon genes, five of which are pseudogenes. There is only a single IFN-β gene. All of these genes lack introns and form a type 1 IFN-α-β superfamily of genes represented as a cluster on the short arm of chromosome 9. IFN-γ, designated type 2 interferon, is encoded by a single gene with three introns and located on chromosome 12.Trophoblast interferon (interferon-τ) is a newly discovered group of interferons functioning in pregnant female ruminants. These proteins are produced in the absence of a known viral stimulus by the trophectoderm. Their major function is to signal specific receptors in the endometrium to maintain an appropriate milieu for the embryo.139 The interferons act by binding specific cell surface receptors.2, 3, 40, 41, 54, 85, 179, 230, 231, 232 The type 1 interferon receptor is present in almost every cell type, albeit at a rather low abundance (100–5000 molecules per cell). In 1994, the IFN-α/β receptor complex was characterized by Novick et al and is physically associated with the cytoplasmic Tyr kinase YAK 1; hence, in addition to ligand binding, it is directly involved in signal transduction.170 This pathway of the IFN-α/β receptor is well characterized after the binding of a type 1 interferon to its receptor; the cytoplasmic signal transducers and activators of transcription (STAT) proteins P84/P91 and P113 undergo Tyr phosphorylation and combine with another cytoplasmic 48 kDa protein (P48) to form the IFN-α stimulated gene factor III complex.49 IGF 3 rapidly translocates to the nucleus and binds to cis-acting interferon stimulated with response elements (ISRE), present in interferon-induced genes, to initiate their transcription.199IFN-γ (type II interferon) binds to a different receptor.4, 44, 113, 129, 150, 153, 156, 157, 206, 214, 215 In 1994, Hemmi et al reported that a specific cofactor encoded on human chromosome 21 is needed for functionality of the interferon-γ receptor and was designated as IFN-γ receptor β chain.15, 18, 23, 103 Today, the International Society for Interferon and Cytokine Research proposed recommendations for interferon receptor nomenclature as follows: interferon ar-2a: interferon ar-2 soluble receptor protein originally reported by Novick et al; interferon ar-2b: interferon ar-2 protein corresponding to the CDNA reported by Novick et al (short form)170; interferon ar-2c: interferon ar-2 protein corresponding to the major CDNA reported by Domanski et al and Lutfalla et al (long form).56, 151 As natural occurring substances, interferons exert a broad spectrum of biological effects (i.e., antiviral, antiproliferative, antitumorous, immunomodulatory, antiinflammatory, and antimicrobial). After binding to interferon receptors, a variety of cellular proteins are induced and account for most of the biological effects of interferon (Table 2).154, 196The mechanisms by which interferons affect viral replication are complex and require synthesis of interferon-induced proteins by target cells.186 Interferons can impair various steps of viral replication, including penetration, transcription, translation, assembly of viruses, and release of viruses from infected cells. Interferon activation of macrophages is an essential component of host defense to the infections. Interferons exert their antiproliferative effects through several mechanisms: (1) Interferons have direct antiproliferative effects on various tumor cells, and (2) activation of cytotoxic T cells of the host immune system such as sensitized T cells, NK cells, and activated macrophages leads to immune-mediated lysis. Further expression of tumor-associated antigens is increased by interferons, thus potentially increasing their recognition by cytotoxic T lymphocytes. Interferon modulation of antibody production may also effect tumor growth.158 Furthermore, interferons, particularly interferon-α and -β, retard the growth and proliferation of tumor cells as well as normal cells by prolonging the cell cycle.81 Type 1 interferons, combined IFN-γ, are synergistic in their antiproliferative effects. Antiproliferative activity of interferons differs in various cell types (e.g., microvascular endothelial cells are extremely sensitive for interferon-α).Immunomodulatory effects of IFN-γ have been relatively well studied compared with effects of type 1 interferons.118, 147, 162, 171, 197 IFN-γ is the classic macrophage-activating factor. The most prominent immunologic effect of interferon is modulation of MHC antigen expression.95 The type 1 and type 2 interferons may have antagonistic immunomodulatory effects, while acting synergistically for antiviral or antiproliferative activity.Immunologic diseases are being associated with the distribution of the T-helper (Th) cell population. IFN-α stimulates production of T-1 cells, which primarily make IFN-γ and IL-2 at the expense of Th-2 cells. Th-2 cells primarily make IL-4 and IL-5.198 IFN-α is known to work in several diseases linked to Th-1– mediated pathophysiology. For example, psoriasis may be exacerbated by IFN-α therapy. IFN-γ and IL-2 show mainly proinflammatory activities. IFN-α increases the frequency of IFN-γ secreting CD4 Th cells and antagonizes the suppressive effect of IL-4 on IFN-γ production. These mechanisms may explain the beneficial effects of IFN-α in the treatment of diseases characterized by excess Th-2 cells, such as early AIDS, basal cell carcinoma, certain allergic diseases, and hypereosinophilic syndrome. For the latter, it has been shown that eosinophils on various eosinophilic disorders express IFN-α receptors.6 IFN-α receptors enable the inhibition of the release of eosinophil granule proteins such as eosinophilic cationic protein (ECP), neurotoxin (EDN) or IL-5. Allergic diseases caused by excess IL-4 and immunoglobulin E production or intracellular parasitic diseases may also respond to IFN-α therapy. IFN-α plays an important role in T-cell differentiation towards a Th-1 type of immune response, which may be of importance in the treatment of viral infection and diseases dominated by the Th-2 pathway.6, 107, 222Increasing evidence shows that IFN-α interferes with the synthesis of various cytokines, and in some cases acts as an antiinflammatory agent (e.g., by induction of interleukin10).Interferons are among the most active biological substances. Based on their natural activity, limited toxicity, and availability through recombinant DNA technology, interferons have been studied for therapeutic efficacy in a number of conditions. By 1997, the U.S. Food and Drug Administration approved interferons for some clinical indications. IFN-α has been approved for treatment of viral infections including hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV; condylomata acuminata), and malignancies including hairy cell leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, malignant melanoma (adjuvant therapy), and Kaposi's sarcoma in HIV-infected patients. IFN-γ has been approved for prophylactic use in patients with chronic granulomatous disease to prevent recurrence of bacterial infection. Two years ago, IFN-β was approved for the treatment of patients with multiple sclerosis in the United States. In addition, interferons have demonstrable efficacy in laryngeal papillomatosis, herpes zoster, early stages of HIV infection, multiple myeloma, and basal cell and cutaneous squamous cell carcinoma.60, 75, 242 The world-wide registration status of IFN-α is documented in Table 3. In some European countries and in Japan, interferons are approved for an additional number of these diseases. Interferon-β derived from fibroblasts is available for intravenous application in severe herpes virus diseases and as adjuvant topical therapy in small condylomata acuminata.