Ciclesonide inhibits TNFα- and IL-1β-induced monocyte chemotactic protein-1 (MCP-1/CCL2) secretion from human airway smooth muscle cells

Abstract

Monocyte chemotactic protein-1 (MCP-1) is a member of the CC family of cytokines. It has monocyte and lymphocyte chemotactic activity and stimulates histamine release from basophils. MCP-1 is implicated in the pathogenesis of inflammatory diseases, including asthma. The airway smooth muscle (ASM) layer is thickened in asthma, and the growth factors and cytokines secreted by ASM cells play a role in the inflammatory response of the bronchial wall. Glucocorticoids and β2-agonists are first-line drug treatments for asthma. Little is known about the effect of asthma treatments on MCP-1 production from human ASM cells. Here, we determined the effect of ciclesonide (a glucocorticoid) and formoterol (a β2-agonist) on MCP-1 production from human ASM cells. TNFα and IL-1β induced MCP-1 secretion from human ASM cells. Formoterol had no effect on MCP-1 expression, while ciclesonide significantly inhibited IL-1β- and TNFα-induced MCP-1. Furthermore, ciclesonide inhibited IL-1β- and TNFα-induced MCP-1 mRNA and IL-1β- and TNFα-induced MCP-1 promoter and enhancer luciferase reporters. Western blots showed that ciclesonide had no effect on IκB degradation. Finally, ciclesonide inhibited an NF-κB luciferase reporter. Our data show that ciclesonide inhibits IL-1β- and TNFα-induced MCP-1 production from human ASM cells via a transcriptional mechanism involving inhibition of NF-κB binding.

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

“…For example, IL-1b was reported to be a potent inducer of other cytokines, including IL-8 or CCL2. [40][41][42] We found glomerular monocyte accumulation, significantly elevated renal IL-1b levels, and pharmacological IL-1 receptor blockade that protected Phox-deficient mice from NCGN, making Phoxdysregulated IL-1b generation an attractive candidate mechanism for disease acceleration. In the presence of ANCA, Phox deficiency caused accelerated monocyte caspase-1 activity and increased IL-1b generation in vitro.…”

Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

“…These include genes that primarily affect noninflammatory pathways such as CD38, an NF-B target that increases ASM contractility and is repressed by GCs (25,29,59), and RGS2 (66), whose induction by GR is similarly implicated in modulating ASM contraction (25). In addition, a host of genes with presumptive proinflammatory activity such as IL6, CCL2, and RANTES, among others, are potently repressed in ASM by steroid treatment (2,45). Tethering-based interactions between GR and inflammatory transcription factors such as NF-B, resulting in GR-mediated recruitment of repressive complexes, are frequently viewed as contributing to transcriptional repression by GCs in HASM (4).…”

Chemokine Regulation of Angiogenesis During Wound Healing

“…31,32 CXCL2 is a well-known mediator of neovascularization and signals through CCR2 and CCR3 receptors to promote endothelial cell migration and cord formation in vitro.…”