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The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs

Nature Medicine volume 8, pages 1421–1426 (2002)Cite this article

Abstract

Can T cells be directly activated to de novo gene expression by gonadotropin-releasing hormone-II (GnRH-II), a unique 10-amino-acid neuropeptide conserved through 500 million years of evolution? GnRH-II, which has been identified in mammals1,2, shares 70% homology with the mammalian hypothalamic neurohormone GnRH (GnRH-I), the primary regulator of reproduction, but is encoded by a different gene3. Although both neuropeptides are produced mainly in brain, their localization1,2 and promoter regulation4,5 differ, suggestive of distinct functions. Indeed, GnRH-II barely affects reproduction1 and its role in mammalian physiology is unknown. We find here that human normal and leukemic T cells produce GnRH-II and GnRH-I. Further, exposure of normal or cancerous human or mouse T cells to GnRH-II or GnRH-I triggered de novo gene transcription and cell-surface expression of a 67-kD non-integrin laminin receptor that is involved in cellular adhesion and migration and in tumor invasion and metastasis. GnRH-II or GnRH-I also induced adhesion to laminin and chemotaxis toward SDF-1α, and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GnRH-I. A specific GnRH-I-receptor antagonist blocked GnRH-I- but not GnRH-II-induced effects, which is suggestive of signaling through distinct receptors. We suggest that GnRH-II and GnRH-I, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance.

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Figure 1: GnRH-I and GnRH-II genes and peptides are expressed in human T cells and can activate T cells to produce the laminin receptor.
Figure 2: GnRH-II and GnRH-I induce adhesion of human T cells to laminin and increase their in vitro migration toward the chemoattractant SDF-1α.
Figure 3: EL-4 T-lymphoma cells express the 67 kD LR, and GnRH stimulation increases its expression and enhances entry of the T-lymphoma in vivo into the bone marrow and spleen of recipient mice.

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Acknowledgements

We thank E. Flesher of the Sackler Faculty of Medicine, Tel Aviv University, for the EL-4 T-lymphoma cells and helpful discussions, and H. Otmi and R. Margalit for expert animal handling and surgery. This study was supported by grants from the Volkswagen-Stiftung Foundation and the Rochlin Foundation (to M.L.) and from the Israel Science Foundation (to Y.K).

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  1. Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel

    Alon Chen, Yonatan Ganor, Shai Rahimipour, Nurit Ben-Aroya, Yitzhak Koch & Mia Levite

  2. The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Mia Levite

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  1. Alon Chen
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Correspondence to Yitzhak Koch or Mia Levite.

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Chen, A., Ganor, Y., Rahimipour, S. et al. The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs. Nat Med 8, 1421–1426 (2002). https://doi.org/10.1038/nm1202-801

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