Interferon-y INF

Specific cellular immunity is a type of (more specialized) acquired immunity which is based primarily on T lymphocytes. Several subpopulations of T lymphocytes are differentiated in the thymus, where one subset has identical structures on the cell surface to recognize a specific set of antigen. Each subpopulation performs different effector functions. The dominant T-cell type involved is the so-called cytotoxic T lymphocyte. In addition, T-helper cells are important for enhancing the immune response. By synthesizing and secreting various cytokines such as interferon y (INF-y or interleukin 2 (IL-2), T-lymphocytes also have an important role in controlling other major parts of the immune system. 

Osteoclasts are multinucleated cells found on the endosteal surface of bone, in Haversian systems and periosteal surfaces. PTH activates osteoclasts (indirectly via osteoblasts that possess PTH receptors). Calcitonin is a potent inhibitor of osteoclast activity. Local cytokine factors, including interleukin-1 (IL-1), tumour-necrosis factor (TNF), TGF- 0 and interferon-y (INF-y), are important regulators. Osteoclast resorption of bone releases collagen peptides, pyridinoline cross-links and calcium from the bone matrix, through the action of lysosomal enzymes (collagenases and cathepsins). The collagen breakdown products in serum and urine (e.g. hydroxyproline) can be used as biochemical markers. 

Many of the manifestations of intraabdominal infections, particularly peritonitis, result from cytokine activity. Inflammatory cytokines, such as tumor necrosis factor a (TNF-a), interleukin 1 (IL-1), IL-6, IL-8, and interferon-y (INF-y), are produced by macrophages and neutrophils in response to bacteria and bacterial products or in response to tissue injury resulting from the surgical incision. These cytokines produce wide-ranging effects on the endothelium of organs, particularly the liver, lungs, kidneys, and heart. With uncontrolled activation of these mediators, sepsis may result (see Chap. 117). 

Abbreviations used tumor necrosis factor-a (TNF-a), interferon-y (INF-y), interleukin-ip (IL-1P), sphingosine kinase (SK), protein kinase C (PKC), sphingomyelinase (SMase), extra-cellular-regulated mitogen-activated protein kinase (ERK), stress-activated protein kinase (SAPK), ceramide activated protein kinase (CAPK), ceramide activated protein phosphatase (CAPP), mitogen activated kinase (MEK), phosphatidylinositol-3-kinase (PI3K), phospholipase C (PLC), phospholipase D (PLD), SIPR (SIP receptor). 

Toxicity of lipoplex is a major problem limiting efficiency and utility. Dow et al. found that injection of small amounts of lipoplex induced CD69 expression on multiple cell types and activation of THl cytokines fiom both lung and spleen mononuclear cells. Neither naked plasmid DNA nor the lipids themselves induced this stereotypic inflammatory response (10). In mice, interferon-y (INF-y) levels peaked at 8 hr after injection and returned to control levels by 24 hr. In INF-y knockout mice, peak levels of transgene expression were one to two orders of magnitude greater than in wild-type controls, although the rate of decline in expression did not differ (S.Dow, personal communication). Consistent with a... 

Interferon a, P, y INF-Ra, INF-RP, INF-Ry, receptors with associated tyrosine kinase... 

Interferon- gamma (INF-y) Antitumor Human (Phase I trial) Inhalation Inhalation increases alveolar concentration of INF-y without major side effects [99]... 

Interferon-y and/or interleukin-ip or a combination of INF-y and TNF-a induced nitric oxide synthase in rat type II pneumocytes in vitro the production of nitric oxide was inhibited by 2 -monomethyl-L-arginine in a dose-dependent manner (Punjabi et al. 1994). 

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins, chemokines, tumor necrosis factors, interferons (INF-a, -0, and -y), colony-stimulating factors, growth factors, neuropoietins, and neurotrophins (see Table 13.4). 

Interferon (INF)2 (several subtypes) INF a,p,y Promote differentiation and proliferation of lymphocytes... 

One possibility is an additional covalent modification, such as phosphorylation of serine 727 of STAT 1, which occurs only in response to INF-y. Dephosphorylation may also contribute to the specificity of INF signalling, because the tyrosine phosphatase, FTP ID, which is associated with IFNARl (the interferon-a receptor 1) participates in the response to INF-cc/p. ... 

Interferons, IFN s belong to a group of cytokines of Mr in the range of 15.000 to 30.000. There are three types of interferons, INF-a, INF-/3 and INF-y. They are released by cells on exposure to inducing agents, such as viruses. A special property of the INF s is their anti-viral activity. 

Although it is not possible to delineate the mechanisms by which interferon beta-lb exerts its activity in MS. it is known that the interferon binds to specific receptors on cell surfaces and induces the expression of a number of interferon-induced gene products, such as 2. 5 -oligoadenylate synthetase and protein kinase. Additionally, interferon beta-lb blocks the synthesis of INF-y. which is believed to be involved in MS attacks. 

The EC-SOD is less responsive to oxidant stress than MnSOD. However, in human fibroblasts, the level of SOD3 is elevated by interferon (IFN)-y and IL-1 [94]. In rat alveolar type II pneumocytes, TNF-a and INF-y elevate SOD3 expression via activation of NF-kB [95]. In vascular smooth muscle cells, expression of EC-SOD is induced by INF-yand IL-4 [96]. Angiotensin II up-reg-ulates EC-SOD synthesis in vascular smooth muscle cells [30]. 

Ultrastmctural studies suggest that endothelial and/or epithelial injury precedes inflammation and fibrosis in early SSc-ILD (51). Thereafter, both proliferation of myofibroblasts and the overdevelopment of capillary microvessels seem to be involved in progressive lung fibrosis (66). T lymphocytes may play a fundamental role. T-cell responses to epitopes of DNA topoisomerase I are restricted, both in healthy subjects and in those with SSc (67-69). Thus, the anti-topoisomerase antibody may provoke a pathogenetic immune response in individuals with responsive T-cell clones. Lung tissue of patients with SSc-ILD displays lymphoid follicles with germinal centers and CD4 T cells of both THl and TH2 subsets that express the hallmark profile of cytokines [interleukin-4 (EL-4), EL-5, and y-interferon (INF-y)] in balanced numbers at the mRNA level (10), as well as accumulation of memory type lymphocytes (70). In BAL, patients with SSc-ELD show a predominance of CD8 T cells that produce Th2 cytokines, most notably EL-4, in contrast to those with no ILD (71). 

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