Signaling Pathways and Transcription Factors Involved in Asthma Pathogenesis

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Soluble mediators may play important roles in the sensitization and triggering of asthmatic responses, but they only do so by acting through specific receptors. Binding to a specific receptor by any cognate ligand normally transduces a signal to the nucleus to transcribe, or block the transcription of, a gene or genes via one or more intracellular biochemical pathways. Steps along a pathway are referred to as pathway intermediates, and those intermediates directly responsible for binding to DNA elements in the nucleus and affecting mRNA expression are called transcription factors. When a toxicant is encountered during pregnancy, the potential exists for signal transduction pathways involved in allergic sensitization to be altered. Alterations could exist in many forms, including receptor blockade, receptor antagonism (sending a negative signal), inhibition or activation of pathway intermediates, or interference with the activity of transcription factors. Any of these events has the potential to change gene expression patterns and initiate pathogenesis, including the generation of asthma.

Allergic sensitization of T cells requires an allergen-specific signal transduced by the TCR and a nonspecific costimulatory signal (Mueller et al. 1989). TCR signals received from APC in the absence of costimulation result in allergenic tolerance or anergy (Schwartz 1990). At least two costimulatory pathways are involved in allergic sensitization. The first is the CD28/B7 pathway. CD28 is con-stitutively expressed on T cells (Figure 14.3), and its receptors are B7-1 (CD80) and B7-2 (CD86) on APC (Figure 14.9). The induction of airway eosinophilia and inflammation requires the ligation of both B7-1 and B7-2 by T cells (Harris et al. 1997; Mark et al. 1998; Tsuyuki et al. 1997). Overexpression of B7-1 and B7-2 in alveolar macrophages from asthmatics has been reported (Agea et al. 1998), and allergen-induced T cell activation involves B7-2, as does expression of IL-5 in human asthmatic airways (Larche et al. 1998). The second costimulatory system involved in allergic sensitization is the CD40/CD40L (CD154) system. When CD40L is expressed on activated T cells and binds to CD40 on B cells, B cell isotype switch machinery is turned on. This machinery includes activation of the nuclear transcription factor called nuclear factor kB (NFkB), which is required for IgE production (Corry and Kheradmand 1999; Kay, 2001). The cascade of events involved in the switch to IgE production also relies on the cytokines IL-4 and IL-13. Interestingly, each of these TH2 cytokines binds to the high-affinity a chain of the IL-4 receptor (reviewed in Wills-Karp et al. 1998). STAT-6 and c-maf are two transcription factors that are subsequently activated (Kay 2001; Mackay and Rosen 2001) (Figure 14.3 and Figure 14.9).

The biochemical signaling pathway of the IgE receptor FceRI, which includes activation of the protein-tyrosine kinase (PTK) Syk (Mackay and Rosen 2001), should also be scrutinized when assessing immunotoxicant effects on allergic asthma sensitization (Figure 14.2). Toxicants affecting Syk activity might increase FceRI-a signaling, a process central to the involvement of mast cells in the triggering of an asthmatic response. Other pathway intermediates intimately involved in allergic inflammation but yet to be investigated in the development of asthma include GATA transcription factors. Expression of GATA-1 has recently been shown to promote the development and terminal differentiation of eosino-phils, with eosinophil progenitors failing to develop in the fetal livers of GATA-1 deficient mice (Hirasawa et al. 2002). In the same report, GATA-2 was demonstrated to be able to compensate for GATA-1 deficiency in terms of eosinophil development in vivo (Figure 14.5). Recognizing that GATA-1 is a zinc-finger transcription factor, Richter and coworkers found that zinc chelators are able to modulate the labile pool of zinc and regulate gene expression and protein synthesis of C-C chemokines (Richter et al. 2003). In particular, TNFa-stimulated human airway epithelial cells and fibroblasts decreased their production of eotaxin, RANTES and MCP-1 in response to zinc chelators (Figure 14.6). Because of the major roles played by eotaxin and eosinophils in the pathogenesis of asthma, dysregulation of the GATA-1 and GATA-2 transcription factors may also be important to investigate as endpoints in the effects of environmental toxicants on the developing immune system.

Other potential intracellular players in asthma pathogenesis include members of the suppressor of cytokine signaling (SOCS) family. Because this family of proteins is known to be involved in the pathogenesis of many inflammatory diseases, and SOCS-3 is predominantly expressed in TH2 cells, Seki and colleagues investigated the role of SOCS-3 in TH2-related allergic diseases. The authors showed a strong correlation between SOCS-3 expression, serum IgE levels in allergic human patients, and the pathology of asthma and atopic dermatitis (Seki et al. 2003). Moreover, SOCS-3 transgenic mice developed pathological features characteristic of asthma. These transgenic mice exhibited increased TH2 responses, whereas decreased TH2 responses were elicited in dominant-negative mutant SOCS-3 trans-genic mice, as well as in mice with a heterozygous deletion of Socs3. Because these data suggest a critical role for SOCS-3 in the onset and maintenance of asthma, it would be prudent to monitor this marker in response to gestational exposures during critical windows of development (Figure 14.3).

We have shown that the multiple levels of complexity of asthmatic inflammation involve the bronchial airways, the circulation and lymphoid systems, cell-cytokine networks, and intracellular signaling. Understanding how maternal influences may affect fetal asthma sensitization will require an integrated view of the components of the asthma sensitization engine detailed earlier. For an integrated overview of how all of the parts of that engine fit together, Figure 14.1 through Figure 14.9 can be laid out into a grid, as shown in Figure 14.10. The contribution of the cells and molecules described above to fetal asthma sensitization will be discussed in the next section.

The Asthma Sensitization Engine An Integrated Overview of its Components

Circulatory and Lymphoid Systems

Circulatory and Lymphoid Systems

The Asthma Sensitization Engine An Integrated Overview of its Components

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The Cell-Cytokine Networks of Asthma

The Cell-Cytokine Networks of Asthma

Intracellular Signaling

Figure 14.10 The asthma sensitization engine. For an integrated, birdseye view of how the bronchial airways, circulatory and lymphoid systems, cell-cytokine networks, and intracellular signal transduction pathways involved in asthmagenesis interact, Figure 14.1 through Figure 14.9 can be laid out in the grid pattern depicted here.

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