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Polarization of Primary Human Monocytes by IFN- Induces Chromatin Changes and Recruits RNA Pol II to the TNF- Promoter¹

Division of Allergy Immunology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Monocyte polarization by IFN- or IL-4 drives a complex series of cellular responses leading to increased intracellular killing (IFN-) or enhanced healing (IL-4) among other functional responses. We studied the effect of IL-4 and IFN- polarization on histone modifications at the TNF- locus in human primary monocytes. IFN- polarization markedly increased the expression of TNF-, whereas IL-4 treatment decreased the expression. We found that IFN- alone increased histone H4 acetylation at the TNF- promoter. The effect of IFN- on TNF- expression was durable upon cytokine washout and even repolarization with IL-4. Concordantly, IFN--mediated H4 acetylation was also durable. IFN- recruited activating transcription factor-2 via p38 to the TNF- promoter, but inhibition of p38 had minimal effect on H4 acetylation. In a novel finding, we found that IFN- recruited RNA Pol II to the human TNF- promoter via ERK signaling, but did so without initiating transcription, leading to a poised condition. These studies provide an important perspective on monocyte polarization. Polarization by IFN- has a durable effect on TNF- expression, and histone acetylation may provide a mechanism for persistence of the effect.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI051323 and R01 AI44127. S.G. was supported in part by American Academy of Allergy, Asthma and Immunology’s Strategic Training in Allergy Research (ST*AR) Award, University of Pennsylvania School of Medicine Cancer Research Institute Predoctoral Emphasis on Pathways in Tumor Immunology Training Grant, and the Goldie Simon Award.

² Address correspondence and reprint requests to Dr. Kathleen E. Sullivan, Division of Allergy and Immunology, Children’s Hospital of Philadelphia, ARC 1216, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: sullivak{at}mail.med.upenn.edu

³ Abbreviations used in this paper: ATF, activating transcription factor; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; Ct, cycle threshold; HDAC, histone deacetylase.