Synergism between fibronectin and transforming growth factor-??1 in the production of substance P in monocytes of patients with myelofibrosis

摘要

Substance P (SP), also considered a proinflammatory cytokine, as well as others such as transforming growth factor-??1 (TGF-??1) and interleukin-1 (IL-1), and the extracellular matrix protein fibronectin (FN) have been associated with the pathophysiology of myelofibrosis. SP is encoded by the TAC1 gene. The relationships among SP, TGF-??1, IL-1 and FN are poorly understood. This study determined the mechanisms for concomitant production of IL-1, TGF-??1 and SP and also determined the synergistic role of FN in SP release. Enzyme-linked immunosorbent assay (ELISA) indicated increased levels of SP and TGF-??1 in the blood of patients with myelofibrosis. Monocytes, shown to be activated in patients with bone marrow (BM) fibrosis, expressed the TAC1 gene for SP release, in a nuclear factor-??B (NF??B)-dependent manner. Reporter gene assay with the 5' regulatory region of TAC1 indicated its expression by high levels of FN and TGF-??1. Immunohistochemical studies of paraffin-embedded BM biopsies from patients with myelofibrosis, and age-matched controls without fibrosis, indicated co-localization of SP and its receptor neurokinin-1 (NK1). In summary, myelofibrotic monocytes have autocrine loops that stimulate the release of SP and TGF-??1, and that are potentiated by fibronectin. The FN-mediated induction of SP in turn stimulates monocytes through autostimulation by NK1 receptors. These findings, combined with those of previous studies, demonstrate an adhesion-mediated NF??B/IL-1/TGF-??1 axis that can be initiated by increased FN in patients with myelofibrosis for the production of SP. These findings show how TGF-??1 and SP production are coupled, and suggest new therapeutic targets to reverse immune-mediated fibrosis. ? 2013 Informa UK, Ltd.