Abstract
Aging and dysregulation of immune responds are closely associated through a complicated but unclear mechanism. Although many theories have been proposed as overall dysregulation involved in aging, mechanisms such as efficiency of DNA repairing, over-expression of transcription factors (such as NF-κB family), and shift of cell types, are among many factors that contribute to and affect aging process. It is of great interests to understand the possible mechanism that is involved in aging immune system. Here, we report that the inducible genes Il2 and Csf2 are increased as T cells undergo activation and aging. Of particular note were the findings that the relative composition of the circulating CD4+ T cell population changes as animals mature with an increased percentage of the population being memory/effector type cells. In addition, mRNA levels of NF-κB family genes that are essential elements for cytokine activation in adult mice and activated T cells are significantly increased. We have demonstrated that the expression of inducible genes is accompanied by increased memory/effector type cells and by increased expression level of NF-κB family genes during cell activation and development.
Similar content being viewed by others
Abbreviations
- PMA/I:
-
Phorbol 12-myristate 13-acetate and calcium ionophore
- FACS:
-
Fluorescent-activated cell sorting
- Il2 :
-
Interleukin-2
- Csf2 :
-
Granulocyte-macrophage colony-stimulating factor
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- Sirt:
-
Sirtuin
References
Desai A, Grolleau-Julius A, Yung R (2010) Leukocyte function in the aging immune system. J Leukoc Biol 87(6):1001–1009. doi:10.1189/jlb.0809542
Grolleau-Julius A, Abernathy L, Harning E, Yung RL (2009) Mechanisms of murine dendritic cell antitumor dysfunction in aging. Cancer Immunol Immunother 58(12):1935–1939. doi:10.1007/s00262-008-0636-9
Ernst DN, Hobbs MV, Torbett BE, Glasebrook AL, Rehse MA, Bottomly K, Hayakawa K, Hardy RR, Weigle WO (1990) Differences in the expression profiles of CD45RB, Pgp-1, and 3G11 membrane antigens and in the patterns of lymphokine secretion by splenic CD4+ T cells from young and aged mice. J Immunol 145(5):1295–1302
Lerner A, Yamada T, Miller RA (1989) Pgp-hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur J Immunol 19(6):977–982
Nagelkerken L, Hertogh-Huijbregts A, Dobber R, Drager A (1991) Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4 + T cells. Eur J Immunol 21(2):273–281
Kurashima C, Utsuyama M (1997) Age-related changes of cytokine production by murine helper T cell subpopulations. Pathobiology 65(3):155–162
Utsuyama M, Hirokawa K, Kurashima C, Fukayama M, Inamatsu T, Suzuki K, Hashimoto W, Sato K (1992) Differential age-change in the numbers of CD4+ CD45RA+ and CD4+ CD29+ T-cell subsets in human peripheral-blood. Mech Ageing Dev 63(1):57–68
Cuddapah S, Barski A, Zhao K (2010) Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol 22(3):341–347. doi:10.1016/j.coi.2010.02.007
Phyllis-Jean L, Laura H, Lisa T, Xiaohong Z, Susan S (1997) From naive to effector-alterations with aging. Immunol Rev 160(1):9–18
Huang MC, Liao JJ, Bonasera S, Longo DL, Goetzl EJ (2008) Nuclear factor-kappa B-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J 22(7):2142–2150. doi:10.1096/fj.07-103721
Rooney JW, Sun YL, Glimcher LH, Hoey T (1995) Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. Mol Cell Biol 15(11):6299–6310
Helenius M, Kyrylenko S, Vehvilainen P, Salminen A (2001) Characterization of aging-associated up-regulation of constitutive nuclear factor-kappa B binding activity. Antioxid Redox Signal 3(1):147–156. doi:10.1089/152308601750100669
Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136(1):62–74. doi:10.1016/j.cell.2008.10.052
Salminen A, Kaarniranta K (2009) NF-kappaB signaling in the aging process. J Clin Immunol 29(4):397–405. doi:10.1007/s10875-009-9296-6
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305(5682):390–392. doi:10.1126/science.1099196
Wakikawa A, Utsuyama M, Wakabayashi A, Kitagawa M, Hirokawa K (1999) Age-related alteration of cytokine production profile by T cell subsets in mice: a flow cytometric study. Exp Gerontol 34(2):231–242
Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint J-P, Labalette M (2006) Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4 + versus effector memory and terminally differentiated memory cells in CD8 + compartment. Mech Ageing Dev 127(3):274–281
Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG (2009) Interleukin-1 and IL-23 induce innate IL-17 production from T cells, amplifying Th17 responses and autoimmunity. Immunity 31(2):331–341
Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR (2007) Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 100(11):1659–1666. doi:10.1161/01.RES.0000269183.13937.e8
Helenius M, Hanninen M, Lehtinen SK, Salminen A (1996) Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-kB transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28(3):487–498. doi:10.1006/jmcc.1996.0045
Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A (2007) Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293(1):H37–H47. doi:10.1152/ajpheart.01346.2006
Korhonen P, Helenius M, Salminen A (1997) Age-related changes in the regulation of transcription factor NF-kappa B in rat brain. Neurosci Lett 225(1):61–64
Radak Z, Chung HY, Naito H, Takahashi R, Jung KJ, Kim HJ, Goto S (2004) Age-associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise. FASEB J 18(6):749–750. doi:10.1096/fj.03-0509fje
Zhang J, Dai J, Lu Y, Yao Z, O’Brien CA, Murtha JM, Qi W, Hall DE, Manolagas SC, Ershler WB, Keller ET (2004) In vivo visualization of aging-associated gene transcription: evidence for free radical theory of aging. Exp Gerontol 39(2):239–247. doi:10.1016/j.exger.2003.10.024
Lafontaine-Lacasse M, Richard D, Picard F (2010) Effects of age and gender on Sirt 1 mRNA expressions in the hypothalamus of the mouse. Neurosci Lett 480(1):1–3. doi:10.1016/j.neulet.2010.01.008
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. doi:10.1038/nature01960
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000):686–689. doi:10.1038/nature02789
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23(12):2369–2380. doi:10.1038/sj.emboj.7600244
Acknowledgments
This work was funded by an Epigenomics Capacity Development Grant from Bioplatforms Australia (http://www.bioplatforms.com.au/). Project supported by the National Science Foundation of China (Grant No. 31172185) for Chao Sun. A scholarship from the Chinese Scholarship Council was awarded to YL. The authors declare that they have no competing financial interests. This funding does not alter our adherence to all the MBR policies on sharing data and materials.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, Y., Ohms, S.J., Sun, C. et al. NF-κB controls Il2 and Csf2 expression during T cell development and activation process. Mol Biol Rep 40, 1685–1692 (2013). https://doi.org/10.1007/s11033-012-2219-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-2219-2