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Activated Polymorphonuclear Leukocytes Rapidly Synthesize Retinoic Acid Receptor-

Christian C. Yost^1,4, Melvin M. Denis^3,4, Stephan Lindemann⁴, Frederick J. Rubner^1,4, Gopal K. Marathe⁴, Michael Buerke⁵, Thomas M. McIntyre^2,3,4, Andrew S. Weyrich^2,4, and Guy A. Zimmerman^2,4

¹ Department of Pediatrics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112
² Department of Internal Medicine, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112
³ Department of Pathology, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112
⁴ Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112
⁵ Department of Internal Medicine III, Martin Luther University, 40 06097 Halle-Wittenburg, Germany

Address correspondence to Guy A. Zimmerman, Program in Human Molecular Biology and Genetics, University of Utah, 15 North 2030 East Bldg. 533, Rm. 4220, Salt Lake City, UT 84112. Tel.: (801) 585-0727; Fax: (801) 585-0701; email: guy.zimmerman{at}hmbg.utah.edu

In addition to releasing preformed granular proteins, polymorphonuclear leukocytes (PMNs) synthesize chemokines and other factors under transcriptional control. Here we demonstrate that PMNs express an inducible transcriptional modulator by signal-dependent activation of specialized mechanisms that regulate messenger RNA (mRNA) translation. HL-60 myelocytic cells differentiated to surrogate PMNs respond to activation by platelet activating factor by initiating translation and with appearance of specific mRNA transcripts in polyribosomes. cDNA array analysis of the polyribosome fraction demonstrated that retinoic acid receptor (RAR)-, a transcription factor that controls the expression of multiple genes, is one of the polyribosome-associated transcripts. Quiescent surrogate HL60 PMNs and primary human PMNs contain constitutive message for RAR- but little or no protein. RAR- protein is rapidly synthesized in response to platelet activating factor under the control of a specialized translational regulator, mammalian target of rapamycin, and is blocked by the therapeutic macrolide rapamycin, events consistent with features of the 5' untranslated region of the transcript. Newly synthesized RAR- modulates production of interleukin-8. Rapid expression of a transcription factor under translational control is a previously unrecognized mechanism in human PMNs that indicates unexpected diversity in gene regulation in this critical innate immune effector cell.

Key Words: inflammation • innate immunity • gene expression • translation • transcription

Abbreviations used in this paper: mRNA, messenger RNA; mTOR, mammalian target of rapamycin; PAF, platelet activating factor; PMN, polymorphonuclear leukocyte; RACE, rapid amplification of cDNA ends; RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor; UTR, untranslated region.

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