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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
,
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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