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NF-B as a Central Mediator in the Induction of TGF-ß in Monocytes from Patients with Idiopathic Myelofibrosis: An Inflammatory Response Beyond the Realm of Homeostasis¹

Pranela Rameshwar^*, Ramaswamy Narayanan, Jing Qian^*, Thomas N. Denny^,, Cristina Colon^* and Pedro Gascon^2,*

Departments of ^* Medicine-Hematology, Pathology and Laboratory Medicine, and Pediatrics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103; and ^§ Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431

Immune-mediated mechanisms have been implicated in the etiology of idiopathic bone marrow fibrosis (IMF). However, the mechanism remains poorly defined. Compared with healthy controls, IMF monocytes are overactivated, with increased production of TGF-ß and IL-1. TGF-ß is central to the progression of fibrosis in different organs. In the lung, fibrosis is associated with up-regulation of TGF-ß-inducible genes. Because IL-1 and TGF-ß have pro- and antiinflammatory properties and neither appears to regulate the high levels of each other in IMF, we studied the mechanism of this paradigm. We focused on the role of RelA, a subunit of the transcription factor, NF-B that is associated with inflammatory responses. We transiently knocked out RelA from IMF monocytes with antisense oligonucleotides and showed that RelA is central to IL-1 and TGF-ß production and to the adhesion of IMF monocytes. Because the NF-B family comprises subunits other than RelA, we used aspirin and sodium salicylate to inhibit kinases that activate NF-B and showed effects similar to those of the RelA knockout system. It is unlikely that RelA could be interacting directly with the TGF-ß gene. Therefore, we determined its role in TGF-ß production and showed that exogenous IL-1 could induce TGF-ß and adherence of IMF monocytes despite the depletion of NF-B. The results indicate that IL-1 is necessary for TGF-ß production in IMF monocytes, but NF-B activation is required for the production of endogenous IL-1. Initial adhesion activates NF-B, which led to IL-1 production. Through autocrine means, IL-1 induces TGF-ß production. In total, these reactions maintain overactivation of IMF monocytes.

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