Takashi Okamoto Toshifumi Tetsuka Sinichi Yoshida and Takumi Kawabe

Cure Arthritis Naturally

Cure Arthritis Naturally

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Department of Molecular Genetics Nagoya City University Medical School Nagoya 467, Japan

NF-kB is an inducible cellular transcription factor that activates various cellular and viral genes. In resting cells, NF-kB exists as a molecular complex with an inhibitory molecule IkB and is located in the cytosol. On stimulation of the cells by various agents, such as proinflammatory cytokines interleukin (IL)-l and tumor necrosis factor (TNF), IkB is dissociated and NF-kB is translocated to the nucleus and activates the expression of target genes. We found that the redox control mechanism is involved in the DNA-binding activity of NF-kB and that the cellular-reducing catalyst thioredoxin (Trx), together with kinases, is primarily involved as an effector molecule in this signaling pathway. Trx has been found to associate with the redox-sensitive cysteine within the DNA-binding loop of NF-kB. Effects of antioxidants in blocking NF-kB activation can be explained by the involvement of radical oxygen intermediates (ROI) in this pathway. These findings support the idea that redox regulation involving ROI and Trx plays a crucial role in the signal transduction pathway leading to NF-kB activation and thus contributes a great deal to the understanding of the pathogenetic processes of various diseases, such as acquired immunodeficiency syndrome (AIDS), hematogenic cancer cell metastasis, and rheumatoid arthritis (RA), in which NF-kB plays a major role.

I. INTRODUCTION: TRANSCRIPTION FACTOR NF-kB AND ITS BIOLOGICAL FUNCTIONS

NF-kB regulates expression of a wide variety of cellular and viral genes (Gilmore, 1990; Baeuerle and Baichwal, 1997; Baldwin, 1996; Thanos and

Antioxidant and Redox Regulation of Genes

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Maniatis, 1995; Okamoto et al, 1997). These genes include cytokines such as IL-2, IL-6, IL-8, GM-CSF, and TNF, cell adhesion molecules such as ICAM-1 and E-selectin, inducible nitric oxidase synthase (iNOS), and viruses such as human immunodeficiency virus (HIV) and cytomegalovirus. (Schindler and Baichwal, 1994; Okamoto et al., 1989; Stade et al., 1990; Mukaida et al., 1990; Roebuck et al., 1995; Donnelly et al, 1993; Schreck and Baeuerle, 1990; Staynov et al, 1995; Xie et al., 1994; Sen and Baltimore, 1986; Nabel and Baltimore, 1987). Through the causal relationship with these genes, NF-/cB is considered to be involved in the currently intractable diseases such as AIDS, hematogenic cancer cell metastasis, and RA as shown in Fig. 1. Although the genes induced by NF-kB are variable according to the context of cell lineage and are also under the control of other transcription factors, NF-kB is considered to play a major role in the regulation of expression of these genes and thus contributes a great deal to the pathogenesis.

Additionally, another biological action of NF-kB as an inhibitor of apoptosis has been demonstrated, although the molecular mechanism has yet to be elucidated (Beg and Baltimore, 1996; Wu et al, 1996). It is thus hoped that disruption of this antiapoptotic mechanism would make cells more vulnerable to killing. Because proapoptotic signals elicited by TNF

Transcription Factors

Genes

Transcription Factors

Genes

Hematogenic Metastasis ot Cancer

Acquired

Immunodeficiency Syndrome (AIDS)

Figure 1 Relationships between transcription factors and diseases: A pathogenetic paradigm regarding NF-/cB. Transcription factors are causally associated with various genes known to be involved in pathogenetic processes of the relevant diseases. This diagram shows cross-correlations between transcription factors and diseases with attention to transcription factor NF-kB. This diagram indicates that some disease processes may be controlled by modifying the actions of transcription factors.

Diseases

Rheumatoid Arthritis (RA)

Hematogenic Metastasis ot Cancer

Acquired

Immunodeficiency Syndrome (AIDS)

Figure 1 Relationships between transcription factors and diseases: A pathogenetic paradigm regarding NF-/cB. Transcription factors are causally associated with various genes known to be involved in pathogenetic processes of the relevant diseases. This diagram shows cross-correlations between transcription factors and diseases with attention to transcription factor NF-kB. This diagram indicates that some disease processes may be controlled by modifying the actions of transcription factors.

and radiation are also known to stimulate the NF-kB activation pathway, selective inhibition of the antiapoptotic action of NF-kB should augment the antitumor effects of these agents. It has not yet been clarified whether this antiapoptotic action of NF-kB is mediated by the induction of a novel gene(s) as some NF-kB target genes, such as p53, Fas ligand, and c-Myc, have been implicated in apoptosis (Klefstrom et al., 1997; Lane, 1992; Wu and Lozano, 1994). An apparently unexpected action of anti-NF-kb reagents in the protection of neuronal cell death (Grilli et al., 1996) indicates that either the pro- or the antiapoptotic action of NF-kB may be determined by the context of the cellular signaling cascade. It is possible that the antiapoptotic action of NF-kB is mediated through direct protein-protein interaction, although the target protein has not been identified. Therefore, the biochemical intervention of NF-kB should conceivably interfere with the pathogenic process and would be effective for treatment.

A hypothesis has been proposed whereby divergent agents activate NF-kB by increasing ROI. Previous studies have revealed that these reducing enzymes, together with ROI, are involved in cell signaling (Holmgren, 1985, 1989; Ziegler, 1985; Allen, 1993). The term "redox regulation" has thus been proposed, indicating the active role of oxido-reductive modifications of proteins in regulating their activities. Oxidation and reduction of bio-molecules are now considered to be "signals" in certain instances and are utilized for the maintenance of cellular homeostasis. In particular, H202 has been implicated as a common second messenger in the various pathways leading to NF-kB activation. This hypothesis is based on several lines of evidence. First, most of the agents activating NF-kB tend to trigger the formation of ROI (Schreck et al., 1991; Schmidt et al., 1995; Los et al., 1995). Second, H202 or organic hydroperoxide has been shown to activate NF-kB in some cell lines in the abscence of any physiological stimulus. Third, antioxidants were shown to be effective in blocking NF-kB activation in response to diverse stimuli (Schreck et al., 1991; Roederer et al., 1990; Suzuki et al., 1992, 1994; Merin et al., 1996; Meyer et al., 1993; Biswas et al., 1993; Packer et al., 1995). However, direct evidence is still lacking to indicate where and how ROI are generated and involved in signaling. This chapter focuses on the nature of redox regulation of NF-kB and its possible therapeutic implications.

II. INVOLVEMENT OF NF-kB IN VARIOUS PATHOLOGIES A. AIDS

The pivotal role of NF-kB in the HIV life cycle, especially in the virus reactivation process within latently infected cells, has been widely accepted.

After activation through intracellular signaling pathways, such as those elicited by the T-cell receptor antigen complex or by receptors for IL-1 or TNF, NF-kB initiates HIV gene expression by binding to the target DNA element within the promoter region of HIV LTR (Okamoto et al., 1989, 1990; Nabel and Baltimore, 1987; Bohnlein et al., 1988). The virus-encoded transactivator Tat is produced and triggers explosive viral replication (Arya et al., 1985; Sodroski et al., 1985; Okamoto and Wong-Staal, 1986).

Because activation of HIV gene expression by cellular transcription factor NF-kB conceptually precedes the production of Tat, NF-kB can be ascribed to be a critical determinant between maintenance and breakdown of the viral latency. Various attempts have been carried out to control the signaling pathways to NF-kB activation in view of the therapeutic intervention of AIDS pathology. For example, antioxidant compounds known to block NF-kB activation cascade have been suggested to be effective in preventing the clinical development of AIDS by blocking HIV replication (Roederer et al., 1990; Suzuki et al., 1992; Merin et al., 1996). Because viral transcription is the only step for the amplification of viral genetic information, the clinically relevant anti-NF-KB compound should be effective in blocking viral replication from the latent status and in substantially decreasing the viral load in virus-infected individuals (Ho, 1998; Perelson et al., 1997; Okamoto, 1995; Tozawa et al, 1995).

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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