Introduction

Cure Arthritis Naturally

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Cytokines are small intercellular signaling molecules that have emerged as important targets for disease management. Tumor necrosis factor-a (TNF-a) is a potent proinflammatory cytokine. This chapter will review the biology of TNF-a, focusing on its role in chronic inflammatory diseases such as Crohn's disease and rheumatoid arthritis, and also review anticytokine therapies targeted to neutralize TNF-a with emphasis on clinical studies conducted with a monoclonal antibody against TNF-a, infliximab. Published results of clinical trials of other TNF-a-neutralizing agents will also be summarized.

TNF-a

Cytokines are protein mediators, or signaling molecules, that are produced by the cells of the activated immune system. Among these mediators are proinflammatory cytokines including interferons, interleukins, and TNF-a. TNF-a is one of the most important and potent of the inflammatory mediators.

The biological activity of TNF-a was first observed over 100 years ago when physicians noted that, in some cases, cancer patients experienced shrinkage of certain tumors if they also had a serious bacterial infection. In the 1890s, William Coley reported a therapeutic benefit derived from treating patients with inoperable neoplastic disease with repeated inoculations of toxins prepared from gram-positive and gram-negative bacteria (1). These observations came to be attributed to the induction by the bacterial toxins of a host-soluble factor that caused the death, or necrosis, of tumor cells (2). This factor was a proinflammatory cytokine that was eventually named TNF-a. More recently, the wide range of biological activities ascribed to TNF-a suggest that this cytokine is a primary mediator of inflammation and modulates immune responses. Continued, overexpression of TNF-a can result in the chronic inflammation which is characteristic of immune disorders such as Crohn's disease and rheumatoid arthritis.

A wide variety of stimuli can induce TNF-a production by immune cells. Endotoxin, gram-negative bacteria, gram-positive bacteria, tumor cells, viruses such as human immunodeficiency virus (HIV), ionizing radiation, cytokines such as interleukin-1 (IL-1) and interferon-y (IFN-y), phorbol myristyl acetate, and various stress-related responses can all induce TNF-a production in at least some cell types (3). The TNF-a gene is one of the first genes expressed in T or B lymphocytes after these cells have been stimulated through their antigen receptors (4). Interestingly, TNF-a itself induces its own synthesis (5).

TNF-a is produced predominantly in activated macrophages and T cells as a 26-kD transmembrane protein that is released into the circulation as a 17-kD protein subunit after cleavage by proteolytic enzymes. These monomers self-associate into a homotrimer of 51 kD that is the active form of soluble TNF-a (Fig. 1). The 26-kD transmembrane form exists as a bioactive trimer at the cell surface, since transgenic mice that overexpress a modified, proteolysis-resistant form of transmembrane TNF-a develop inflammatory diseases (pro-liferative synovitis, chronic inflammatory arthritis) (6).

TNF-a and other cytokines act as mediators by binding to specific receptors on other cells. Two receptors for TNF-a have been identified and are designated the p55 receptor and the p75 receptor. The p55 receptor is expressed on almost all cell types, whereas the p75 receptor is expressed primarily on hematological, lymphoid, and endothelial cells. The p55 and p75 receptors appear to signal by different pathways, with the p55 receptor signaling most of the proinflammatory and cytotoxic effects of TNF-a, whereas p75 appears to play more of a role in proliferative responses. Soluble forms of the

Figure 1 Schematic illustration of the relationship between TNF-a and receptor activation. TNF-a monomers undergo self-association to form dimers and trimers. Only the trimer form possesses biological activity. The double arrows are asymmetrical to indicate that trimer formation is favored under normal equilibrium. Receptor-ligand binding occurs at the interface between TNF-a monomer subunits.

Figure 1 Schematic illustration of the relationship between TNF-a and receptor activation. TNF-a monomers undergo self-association to form dimers and trimers. Only the trimer form possesses biological activity. The double arrows are asymmetrical to indicate that trimer formation is favored under normal equilibrium. Receptor-ligand binding occurs at the interface between TNF-a monomer subunits.

p55 and p75 receptors are shed from the cell surface, and they may influence the circulating life span and the effects of TNF-a in vivo.

The nature of the interaction between TNF-a and its receptors was revealed by studies using mutant forms of the cytokine. These studies suggested that the receptors bind TNF-a in the cleft between two adjacent subunits of the TNF-a trimer. This was confirmed by Banner et al. (7), who determined that a single TNF-a trimer could simultaneously bind three receptor molecules (see Fig. 1). These results, combined with other studies (8), and the demonstration that the TNF-a trimer is the only active species, strongly suggested that TNF-a binding to cell surface receptors leads to intracellular signaling by cross linking two or three receptors. TNF-a-induced intracellular signaling can lead to the induction of genes and to the production of their gene products.

TNF-a can induce different genes including (a) transcription factors, such as NF-kB and c-jun/AP-1; (b) adhesion molecules, such as E-selectin and intercellular adhesion molecule (ICAM-1); (c) cytokines, such as IL-1, IL-6, and IL-8; (d) cytokine receptors, such as IL-1 receptor and IL-6 receptor; and (e) various inflammatory mediators, such as stromelysin, collagenase, C3 complement protein, and nitric oxide synthase (3,9). TNF-a may also reduce transcription of certain genes. For example, it inhibits collagen gene transcription, which is consistent with its proinflammatory role of inducing matrix met-alloproteinase (MMP-1) that degrades collagen. Some typical cellular responses to TNF-a are listed in Table 1.

Table 1 Some Cellular Responses Attributed to TNF

Cell type

Induces

Macrophage

IL-1, IL-6, IL-8, IL-12 M-CSF, GM-CSF Intracellular calcium Tumor cell killing Cell activation

Generation of superoxide anion Release of platelet-activating factor Nitric oxide synthase IL-1

ICAM-1, VCAM-1

E-selectin, P-selectin

Release of platelet-activating factor

Metalloproteinases

Proliferation

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