Synergism between fibronectin and transforming growth factor-β1 in the production of substance P in monocytes of patients with myelofibrosis.
Substance P (SP), also considered a proinflammatory cytokine, as well as others such as transforming growth factor-β1 (TGF-β1) 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-β1, IL-1 and FN are poorly understood. This study determined the mechanisms for concomitant production of IL-1, TGF-β1 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-β1 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-κB (NFκB)-dependent manner. Reporter gene assay with the 5' regulatory region of TAC1 indicated its expression by high levels of FN and TGF-β1. 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-β1, 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 NFκB/IL-1/TGF-β1 axis that can be initiated by increased FN in patients with myelofibrosis for the production of SP. These findings show how TGF-β1 and SP production are coupled, and suggest new therapeutic targets to reverse immune-mediated fibrosis.
Department of Medicine, UMDNJ-New Jersey Medical School, Newark, NJ, USA. victor.chang@va.gov
Victor T
VT
Chang
Clara
C
Yook
Pranela
P
Rameshwar
D000293:Adolescent; D000368:Aged; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D053582:Interleukin-1alpha / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000097:blood / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000494:pharmacology*; D020298:U937 Cells; D055815:Young Adult
D005353:Fibronectins; D053582:Interleukin-1alpha; C498143:RELA protein, human; D018040:Receptors, Neurokinin-1; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D013373:Substance P