The INDIVIDUALIST

A Wiki about biochemical individuality

Nutrigenomics

See Also

Description

The genes for all 4 subunits of the T-cell antigen receptor (alpha, beta, gamma, and delta) are controlled by distinct enhancers and their enhancer-binding proteins. Marine and Winoto (1991) identified a common TCR regulatory element by demonstrating binding of the enhancer-binding protein GATA3 to the enhancer elements of all 4 TCR genes. GATA3 had been shown in the chicken to be an enhancer-binding protein containing a zinc finger domain. GATA3 mRNA was demonstrated by Northern blot analysis in T cells but not in B cells, macrophages, or HeLa cell lines. GATA3 was abundantly expressed in the T-lymphocyte lineage and was thought to participate in T-cell receptor gene activation through binding to enhancers.

Discussion

CD4 T cells potentiate the inflammatory or humoral immune response through the action of Th1 and Th2 cells, respectively. Zheng and Flavell (1997) found that GATA3 was expressed at a high level in naive, freshly activated cells and Th2 lineage cells, but subsided to a minimal level in Th1 lineage cells as naive cells committed to their Th subset. Antisense GATA3 inhibited the expression of all Th2 cytokine genes in a Th2 clone. In transgenic mice, elevated GATA3 and CD4 T cells caused Th2 cytokine gene expression in developing Th1 cells. Thus, Zheng and Flavell (1997) concluded that GATA3 is necessary and sufficient for Th2 cytokine gene expression.

Interleukin-5 plays a central role in the growth and differentiation of eosinophils and contributes to several disease states, including asthma. There is evidence for a role for cyclic AMP as an immunomodulator: agents that increase intracellular cAMP levels inhibit production of cytokines predominantly produced by T-alpha-1 (Th1) cells such as Interleukin-2 (IL-2) and interferon-gamma. In contrast, the production of Interleukin-5 (IL-5), predominantly produced by Th2 cells, is enhanced by these agents. Siegel et al. (1995) defined precisely the cis-activating elements that regulate inducible murine Interleukin-5 (IL-5) transcription: sequences within the CLE0 element and also a region located between -70 and -59 of the Interleukin-5 (IL-5) promoter that binds the transcription factor Gata3. They speculated that activation via this unique sequence combination confers the specificity needed for selective expression of the [Interleukin 5 (IL5)]? gene in response to elevated levels of intracellular cAMP.

Zhang et al. (1997) demonstrated that GATA3 is critical for expression of the Interleukin-5 (IL-5) gene in Th2 cells. Whereas mutations in the GATA3 site abolished antigen- or cAMP-stimulated IL5 promoter activation in Th2 cells, ectopic expression of GATA3 in Th1 cells or in a nonlymphoid, non-IL5-producing cell line activated the IL5 promoter. Other findings suggested that GATA3 gene expression may play an important role in the balance between Th1 and Th2 subsets in immune responses. Zhang et al. (1997) suggested that inhibition of GATA3 activity has therapeutic potential in the treatment of asthma and other hypereosinophilic diseases.

Links

.