Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: implications for transformation.
BACKGROUND
Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of ATLL patients. However, PTHrP is also up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. The expression of PTHrP and the PTH/PTHrP receptor during immortalization or transformation of lymphocytes by HTLV-1 has not been investigated.


RESULTS
We report that PTHrP was up-regulated during immortalization of lymphocytes from peripheral blood mononuclear cells by HTLV-1 infection in long-term co-culture assays. There was preferential utilization of the PTHrP-P2 promoter in the immortalized cells compared to the HTLV-1-transformed MT-2 cells. PTHrP expression did not correlate temporally with expression of HTLV-1 tax. HTLV-1 infection up-regulated the PTHrP receptor (PTH1R) in lymphocytes indicating a potential autocrine role for PTHrP. Furthermore, co-transfection of HTLV-1 expression plasmids and PTHrP P2/P3-promoter luciferase reporter plasmids demonstrated that HTLV-1 up-regulated PTHrP expression only mildly, indicating that other cellular factors and/or events are required for the very high PTHrP expression observed in ATLL cells. We also report that macrophage inflammatory protein-1alpha (MIP-1alpha), a cellular gene known to play an important role in the pathogenesis of HHM in ATLL patients, was highly expressed during early HTLV-1 infection indicating that, unlike PTHrP, its expression was enhanced due to activation of lymphocytes by HTLV-1 infection.


CONCLUSIONS
These data demonstrate that PTHrP and its receptor are up-regulated specifically during immortalization of T-lymphocytes by HTLV-1 infection and may facilitate the transformation process.
Nadella
Murali V P
MV
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA. Thomas.Rosol@cvm.osu.edu
Shu
Sherry T
ST
Dirksen
Wessel P
WP
Thudi
Nanda K
NK
Nadella
Kiran S
KS
Fernandez
Soledad A
SA
Lairmore
Michael D
MD
Green
Patrick L
PL
Rosol
Thomas J
TJ
D002470:Cell Survival; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis; D018920:Coculture Techniques; D016356:Gene Products, tax / Q000096:biosynthesis; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000096:biosynthesis; D013997:Time Factors; D015854:Up-Regulation
D054405:Chemokine CCL3; D016356:Gene Products, tax; C473449:PTH1R protein, human; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; C514970:tax protein, Human T-lymphotrophic virus 1