Inflammation acute phase proteins

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

Gabay C, Kushner I Acute-phase proteins and other systemic responses to inflammation. New Engl J Med 1999 340 448. 

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. 

Exposure of the SECs to pathogens or cytokines produced by other cells during stress induces activation of the SECs and subsequent production of cytokines, eicosanoids, and/or adhesion molecules. For instance, after activation with EPS, a main component of the walls of gramnegative bacteria and a major inducer of inflammation and non-specific immune functions [20], SECs produce a number of pro- and anti-inflammatory cytokines. Pro-inflammatory cytokines shown to be produced were tumour necrosis factor alpha (TNFa) [26] interleukin-1 alpha/beta(IL-lo/p) [27] the major inducer of acute phase proteins interleukin-6 (IL-6) [28] and the neutrophil chemo-attractant interleukin-8 (IL-8) [29]. Anti-inflammatory cytokines shown to be produced were interleukin-10 (IL-10) [27] and hepatocyte growth factor (HGF) [30]. 

After damage or infection, monocytes and KCs in the area detect the damaged cells or infectious agent and respond with release of primary mediators such as TNFa, IL-1 and some IL-6. These cytokines activate the surrounding cells, that respond with a secondary, amplified release of cytokines. This second wave includes large amounts of IL-6, which induce the synthesis of acute phase proteins in hepatocytes and chemoattractants such as IL-8 and MCP-1. These events will then lead to the typical inflammatory reactions. Both IL-1 and TNFa activate the central regulatory protein of many reactions involved in immunity and inflammation, nuclear factor kappa B (NFkB). These cytokines cause dissociation of NFkB from its inhibitor IkB, which makes translocation of NFkB to the nucleus possible. In the nucleus active NFkB induces the transcription of the second wave cytokines (see also Chapter 7 for the molecular mechanisms of cytokine-mediated cell activation). 

Human ceruloplasmin inhibits lipid autoxidation induced by ascorbate or inorganic Fe It is considered an acute-phase protein with a beneficial effect in inflammation . It was suggested that ceruloplasmin acts as a scavenger of OJ radicals, as it inhibited the reduction of Fe(III)-cytochrome c and of nitroblue tetrazolium in the presence of xanthine oxidase, acetaldehyde, and dioxygen as an OJ-generating system A mechanism without reduction of Cu , similar to that... 

Immunoglobulins, oq-trypsin inhibitor and a2-macroglobulin,k ten or more blood clotting factors and proteins of the complement system all have protective functions that are discussed elsewhere in this book. Hormones, many of them proteins, are present in the blood as they are carried to their target tissues. Many serum proteins have unknown or poorly understood functions. Among these are the acute phase proteins, whose concentrations rise in response to inflammation or other injury. 

Colchicine is another possible candidate for the treatment of Alzheimer s disease. This drug effectively treats familial Mediterranean fever, a condition in which recurrent inflammation and renal amyloidosis occur. Although the amyloid constituents in familial Mediterranean fever and Alzheimer s disease differ, both illnesses involve chronic inflammation, elevated acute-phase proteins, and abnormal processing of a precursor protein leading to deposition of insoluble amyloid fragments. These similarities suggest the potential therapeutic efficacy of colchicine for patients with Alzheimer s disease. 

These are proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the... 

Measurement of acute-phase proteins, especially C-reactive protein, is a useful marker of inflammation in both medical and veterinary clinical pathology. Their presence may also indicate hver failure. 

Acute-phase proteins are a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (or acute-phase response). In response to injury, local inflammatory cells secrete a number of cytokines into the bloodstream, the most notable of which are the interleukins (IL-1, IL-6, IL-8) and TNF-a. The liver responds by producing a large number of acute-phase reactants or reducing the production of others. 

Acute Phase Proteins that are either de novo or markedly elevated after challenge by Proteins infectious disease, inflammation, or other challenge to homeostasis. 

The SLe epitope is expressed on inflammation-induced acute phase proteins which serve as endogenous competitors for selectins and mediate a dampening of the immune response, returning inflammation to homeostasis [53]. Inhibitors of the selectins have been proposed to be useful therapies for treating inflammatory disorders including respiratory distress [54], hypersensitivity responses [55], and surgically induced myocardial ischemic reperfusion injury [56]. Animal studies have shown that the inhibition of selectin-carbohydrate interactions can alleviate these inflammatory responses. 

Generally, it is known that there is a positive correlation between the risk of metabolic syndrome and fruit and vegetable intake, based on the serum concentration of inflammatory markers such as C-reactive protein (CRP). CRP is a globulin that forms a precipitate with the somatic C-polysaccharide of Pneumococcus in vitro and is the most predominant acute phase protein. Then, the appearance of CRP in the serum indicates whether the patients have infectious inflammation or not. 

IL-6 acts on the pituitary to induce adrenocorticotropic hormone (ACTH) release and directly on the adrenal glands to produce glucocorticoids. It is known that different cytoldnes that share gpl30 as a receptor subunit induce serum amyloid A, and potentiate the induction of IL-6 and the activation of the hypothalamic-pituitary-adrenal axis by IL-1. In particular, LIF, OSM, IL-11, and cardiotrophin-1 potentiate the elevation of serum corticosterone and IL-6 levels induced by IL-1. Furthermore, the potentiation of IL-1-induced serum corticosterone levels is not a consequence of the increased serum IL-6 observed after IL-1 administration. Thus either endogenous IL-6 does not mediate IL-l-induced corticosterone increase, or its role may be fulfilled by other cytokines. This is very important in the understanding of the activation of the hypothalamic-pituitary-adrenal axis and that potentiation of acute phase protein synthesis may represent an important feedback regulatory mechanism of inflammation. ... 

Acute phase proteins are plasma proteins produced mainly by hepatocytes. Most APPs are glycoproteins with one or more N-linked complex glycans. Stimulants that commonly induce the acute phase response include tissue injury, rheumatoid arthritis, bacterial infection, inflammation, and neoplasms. Cytokines, notably interleukin-6, induce striking alterations in the concentration and glycosylation pattern of APPs in response to these stimuli [160]. 

Gabay, C. and Kushner, I., (1999). Acute-phase proteins and other systemic response to inflammation. New England Journal of Medicine, 340, 448—454. 

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