DOES CALORIC RESTRICTION ALTER IL-2 TRANSCRIPTION?

Mohammad A. Pahlavani

Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System and Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78284

Received 1/5/98 Accepted 1/9/98

6. CONCLUDING REMARKS

Caloric restriction is known to be an effective method of prolonging the life-span, delaying immunosenescence, and reducing pathology in various strains of rodents. Because caloric restriction has a profound effect on most physiological systems, it is plausible that the modulation of immune function by caloric restriction occurs through changes in gene expression. Gene expression is a cellular process that is fundamental to all cells, and changes in gene expression can markedly affect cellular processes of the organisms. Therefore, it is logical to hypothesize that changes in the expression of the IL-2 gene play a major role in the biological mechanisms responsible for the immunoenhancing effect of caloric restriction. Research from our laboratory supports this hypothesis. We have shown that the expression of IL-2 decreases with age and this decrease was attenuated by caloric restriction. More importantly, we have shown that caloric restriction can alter the expression of IL-2 at the level of transcription. The changes we have observed in the expression of the IL-2 gene could be physiologically important to an organism, because the protein product of this gene plays a critical role in regulating the growth and function of a variety of cells involved in cellular and humoral immune responses. The increase in expression of IL-2 by T cells from caloric restricted rats in response to antigens would be predicted to result in a more robust immune response, which would provide an organism greater protection from foreign antigens.

Although our research clearly demonstrates that caloric restriction can alter the expression of the IL-2 gene at the level of transcription, the molecular mechanisms responsible for the changes in transcription are currently unknown. Our preliminary experiments indicate that the changes in gene transcription are not simply due to anoverall alteration in the transcriptional apparatus of the cell, because not all genes are affected in the same way by caloric restriction. For example, we have observed that while the expression of one gene (IL-2) is affected by caloric restriction, the expression of other gene (e.g., hsp70) is not influenced by caloric restriction. Because the effect of caloric restriction on transcription varies from gene to gene, we hypothesized that caloric restriction alters the transcription of the IL-2 gene through changes in the level and/or activity of the T cell/IL-2-specific transcription factor, i.e., NFAT. We have shown that NFAT binding activity increases with caloric restriction and this increase is correlated with an increase in c-fos expression. Among various signal transduction molecules, the MAPK has been shown to be an important regulator of immediate-early genes (e.g., c-fos and c-jun) transcription. Therefore, our current hypothesis is that caloric restriction may alter the levels/activities of the upstream signaling molecules involved in the Ras/MAPK signaling event. This mechanism would logically explain how caloric restriction enhances IL-2 expression because the MAPK signaling cascade is involved in regulating the transcription of immediate-early genes (e.g., c-fos/jun), in which the gene protein products constitute the nuclear component of the NFAT complex. Although our preliminary results suggest that enhancement in MAPK activation with caloric restriction may underlie the increase in c-fos expression, further investigation is needed to determine how caloric restriction alters signal transduction that leads to T cell activation and IL-2 expression.