Synergism between fibronectin and transforming growth factor-β1 in the production of substance P in monocytes of patients with myelofibrosis

Abstract

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.

Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells

“…Therefore, considering that our results are consistent with these previous studies, it is likely that SP plays an important role in many kinds of tissue fibrosis. Other studies have shown that SP, through NK‐1R, contributes to the progression of myelofibrosis . In addition, NK‐1R antagonists have been shown to protect mice from cytokine‐mediated liver injury and reduce hepatocyte apoptosis .…”

“…Other studies have shown that SP, through NK-1R, contributes to the progression of myelofibrosis. (27) In addition, NK-1R antagonists have been shown to protect mice from cytokine-mediated liver injury and reduce hepatocyte apoptosis. (8,28) In support of these previous findings, our results introduce the novel concept that NK-1R antagonists decrease liver fibrosis in Mdr2 -/mice, reducing biliary damage and increasing the senescence of HSCs.…”

The role of the extracellular matrix in primary myelofibrosis

“…82 One study showed that fibronectin can activate monocytes in patients with MF via increased monocytic production of substance P, a proinflammatory cytokine. 83 …”

Bone marrow fibrosis – the basis of mielofibrosis: pathogenesis, prognostication and antifibrogenic targeted strategies.

“…Умеренное повышение плазменной концентрации TGF-β1 отмечено у мышей (линия Gata1 low ). Десятикратное повышение содержания TGF-β1 в мегакариоцитах отмечалось как у животных, так и у человека [13].…”

“…У мышей (линия Gata1 low ) на фоне повышения содержания TGF-β1 установлена активация Hedgehog и р53 сигнализации в селезёнке и костном мозге. Авторы считают, что ингибирование TGF-β1 сигнального пути у мышей (линия Gata1 low ) способствует снижению выраженности фиброза костного мозга на фоне замедления кроветворения в селезёнке [13].…”