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Prolactin Stimulates Phosphorylation of the Human T-Cell Antigen Receptor Complex and ZAP-70 Tyrosine Kinase: A Potential Mechanism for Its Immunomodulation

Departments of Surgery and Pharmacology, University of Arizona College of Medicine (D.W.M.), Tucson, Arizona 85724; Research Service, VA Medical Center (D.W.M.), Tucson, Arizona 85723; Department of Pharmacology and Toxicology, University of North Dakota School of Medicine & Health Sciences (J.S.K., A.R.B.), Grand Forks, North Dakota 58202

Address all correspondence and requests for reprints to: David W. Montgomery, Ph.D., VA Medical Center, Research Service, Department of Surgery, 3601 S. 6th Avenue, Tucson, Arizona 85723.

Prolactin (PRL) is an immunomodulatory hormone which promotes T-cell activation and proliferation. However, the intracellular mechanisms of this action in normal lymphocytes are unknown. Because the PRL receptor (PRLR) activates several signals also activated by the T-cell antigen receptor (TCR)/CD3 complex, we evaluated whether signaling "cross-talk" occurs between these distinct receptors. Using human thymocytes, human peripheral blood lymphocytes and the rat Nb2 lymphoma T-cell, we found that PRL induced rapid phosphorylation of multiple, TCR/CD3 complex proteins, an event required for lymphocyte activation. Two of these phosphorylated proteins were identified to be CD3 epsilon and ZAP-70 tyrosine kinase, molecules essential for TCR function. Further, PRL induced tyrosyl phosphorylation of ZAP-70 in each population of T-lymphocytes tested, demonstrating for the first time that ZAP-70 is a target of PRL action. Taken together, our results suggest that the PRLR directly affects T-lymphocyte activation by means of signaling cross-talk with the TCR/CD3 complex.

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