Role for TAK1 in cigarette smoke-induced proinflammatory signaling and IL-8 release by human airway smooth muscle cells

Abstract

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease, characterized by a progressive decline in lung function. Airway smooth muscle (ASM) mass may be increased in COPD, contributing to airflow limitation and proinflammatory cytokine production. Cigarette smoke (CS), the major risk factor of COPD, causes ASM cell proliferation, as well as interleukin-8 (IL-8)-induced neutrophilia. In various cell types, transforming growth factor-β-activated kinase 1 (TAK1) plays a crucial role in MAP kinase and NF-κB activation, as well as IL-8 release induced by IL-1β, TNF-α, and lipopolysaccharide. The role of TAK1 in CS-induced IL-8 release is not known. The aim of this study was to investigate the role of TAK1 in CS-induced NF-κB and MAP kinase signaling and IL-8 release by human ASM cells. Stimulation of these cells with CS extract (CSE) increased IL-8 release and ERK-1/2 phosphorylation, as well as Iκ-Bα degradation and p65 NF-κB subunit phosphorylation. CSE-induced ERK-1/2 phosphorylation and Iκ-Bα degradation were both inhibited by pretreatment with the specific TAK1 inhibitor LL-Z-1640-2 (5Z-7-oxozeaenol; 100 nM). Similarly, expression of dominant-negative TAK1 inhibited CSE-induced ERK-1/2 phosphorylation. In addition, inhibitors of TAK1 and the NF-κB (SC-514; 50 μM) and ERK-1/2 (U-0126; 3 μM) signaling inhibited the CSE-induced IL-8 release by ASM cells. These data indicate that TAK1 plays a major role in CSE-induced ERK-1/2 and NF-κB signaling and in IL-8 release by human ASM cells. Furthermore, they identify TAK1 as a novel target for the inhibition of CS-induced inflammatory responses involved in the development and progression of COPD.

Cigarette Smoke Modulates NOD1 Signal Pathway and Human ß Defensins Expression in Human Oral Mucosa

“…Further studies should be preformed to clarify the role of RIP2 in cigarette smoke-related molecular signaling. It has been confirmed that cigarette smoke or CSE exposure could activate NF-κB phosphorylation and induce proinflammatory effects in aerodigestive cells [38,39]. Coincidentally, the present study indicated that cigarette smoke or CSE exposure up-regulated P-NF-κB expression in oral mucosa epithelium and Leuk-1 cells.…”

Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells

“…This result indicates that another signaling pathway regulates ERK-mediated IL-6 expression. ERK is involved in many signaling pathways activated during immune responses, such as those associated with IL-8 expression (Pera et al, 2012), and asthma (Tacon et al, 2012;Yadav et al, 2006). Based on that ERK result, we modified our hypothesis.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Proliferation of human airway smooth muscle in response to PDGF is significantly reduced by the selective TAK1 inhibition, with a dominant-negative inhibitor and small molecule inhibitor, 5Z-7-oxozeaenol (Pera et al, 2011). TAK1 inhibition also inhibits cigarette smoke-induced release of CXCL8 from airway smooth muscle cells (Pera et al, 2012). H. influenzae activates NF-kB and p38 MAPK in human airway epithelial cells via the activation of TAK1 and NIK (Shuto et al, 2001).…”