The peptide hormone prolactin (Prl) exerts a profound effect on both cellular proliferation and differentiation in a variety of tissues, but its role as a immunomodulator has only recently received attention. Its potential importance is supported by the observation that the Prl receptor belongs to the newly identified cytokine receptor superfamily. As a model system for studying how Prl modulates the proliferative response of T lymphocytes, we are using the rat Nb2 T lymphoma cells which require Prl for growth. We isolated a cDNA from Nb2 T cells which showed rapid and dramatic induction by Prl, and found that this cDNA encoded the transcription factor interferon regulatory factor-1 (IRF-1), previously shown to be important in regulating interferon (IFN) gene expression in fibroblasts. We further demonstrated that IRF-1 is induced by the T cell mitogen Con A in murine splenocytes and thymocytes. Our studies suggest that IRF-1 may be a growth-related master switch gene which plays an important regulatory role in T cell activation and proliferation. Very little is known about what regulates IRF-1 gene expression in T cells, what the IRF-1 transcription factor regulates in turn, and how IRF-1 promotes Prl-stimulated cell proliferation. The primary objective of this proposal is to elucidate the role of IRF-1 in T cell activation mediated by Prl and mitogens. Studies are proposed to: 1) analyze the promoter region of the IRF-1 gene, to identify regulatory sequences mediating Prl stimulation, and to characterize the nuclear proteins interacting with the Prl responsive DNA elements; 2) analyze the biochemical properties of IRF-1 protein, with emphasis on posttranslational modification (phosphorylation) as another level of regulation by Prl; and 3) investigate the functional role of IRF-1 in T cell activation and proliferation, by altering IRF-1 levels and examining its effect on cell growth. These studies represent a comprehensive molecular and immunological approach to defining the structure and function relationship of IRF-1 and elucidating the immunoregulatory properties of Prl. Understanding how Prl regulates T lymphocyte function and proliferation through regulation of IRF-1 activation in T cells, will provide new insights into the intricate regulatory circuits between the neuroendocrine and immune systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044625-02
Application #
3246158
Study Section
Immunobiology Study Section (IMB)
Project Start
1992-03-01
Project End
1995-02-28
Budget Start
1993-03-01
Budget End
1994-02-28
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Book McAlexander, M; Yu-Lee, L Y (2001) Sp1 is required for prolactin activation of the interferon regulatory factor-1 gene. Mol Cell Endocrinol 184:135-41
Book McAlexander, M; Yu-Lee, L (2001) Prolactin activation of IRF-1 transcription involves changes in histone acetylation. FEBS Lett 488:91-4
Luo, G; Yu-Lee, L (2000) Stat5b inhibits NFkappaB-mediated signaling. Mol Endocrinol 14:114-23
Herrington, J; Rui, L; Luo, G et al. (1999) A functional DNA binding domain is required for growth hormone-induced nuclear accumulation of Stat5B. J Biol Chem 274:5138-45
Yu-Lee, L Y; Luo, G; Book, M L et al. (1998) Lactogenic hormone signal transduction. Biol Reprod 58:295-301
Yu-Lee, L; Luo, G; Moutoussamy, S et al. (1998) Prolactin and growth hormone signal transduction in lymphohaemopoietic cells. Cell Mol Life Sci 54:1067-75
Smit, L S; Vanderkuur, J A; Stimage, A et al. (1997) Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B. Endocrinology 138:3426-34
Wang, Y; O'Neal, K D; Yu-Lee, L (1997) Multiple prolactin (PRL) receptor cytoplasmic residues and Stat1 mediate PRL signaling to the interferon regulatory factor-1 promoter. Mol Endocrinol 11:1353-64
Yu-Lee, L Y (1997) Molecular actions of prolactin in the immune system. Proc Soc Exp Biol Med 215:35-52
Luo, G; Yu-Lee, L (1997) Transcriptional inhibition by Stat5. Differential activities at growth-related versus differentiation-specific promoters. J Biol Chem 272:26841-9

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