TY - JOUR
T1 - Ceramide-dependent PP2A regulation of TNFα-induced IL-8 production in respiratory epithelial cells
AU - Cornell, Timothy T.
AU - Hinkovska-Galcheva, Vania
AU - Sun, Lei
AU - Cai, Qing
AU - Hershenson, Marc B.
AU - Vanway, Susan
AU - Shanley, Thomas P.
PY - 2009/5
Y1 - 2009/5
N2 - IL-8 is a key mediator in the pathophysiology of acute lung injury. TNFα stimulates IL-8 production in respiratory epithelial cells by activating both the NF-κB and MAP kinase pathways. The precise mechanism by which these pathways are downregulated to terminate IL-8 production remains unclear. We studied the regulatory role of the serine/threonine phosphatase, PP2A, on the signaling pathways involved in IL-8 production from respiratory epithelial cells. Inhibition of PP2A using okadaic acid or gene knockdown using siRNA resulted in an augmentation of TNFα-induced IL-8 production. We also found that PP2A inhibition resulted in prolonged activation of JNK, p38, and ERK resulting in both increased transcriptional activation of the IL-8 promoter and posttranscriptional stabilization of IL-8 mRNA. Because TNFα had been shown to activate ceramide accumulation, and separate studies had linked ceramide with activation of PP2A, we hypothesized the pathway of TNFα-inducing ceramide to activate PP2A comprised an endogenous regulatory pathway. Inhibition of the immediate sphingomyelinase-dependent pathway as well as the de novo synthesis pathway of ceramide production reduced serine/threonine phosphatase activity and augmented IL-8 production. These data suggest that ceramide plays a role in activating PP2A to terminate ongoing IL-8 production. In summary, our data suggest that in respiratory epithelium, TNFα induces ceramide accumulation, resulting in subsequent activation of PP2A, which targets those kinases responsible for transcriptional activation of IL-8.
AB - IL-8 is a key mediator in the pathophysiology of acute lung injury. TNFα stimulates IL-8 production in respiratory epithelial cells by activating both the NF-κB and MAP kinase pathways. The precise mechanism by which these pathways are downregulated to terminate IL-8 production remains unclear. We studied the regulatory role of the serine/threonine phosphatase, PP2A, on the signaling pathways involved in IL-8 production from respiratory epithelial cells. Inhibition of PP2A using okadaic acid or gene knockdown using siRNA resulted in an augmentation of TNFα-induced IL-8 production. We also found that PP2A inhibition resulted in prolonged activation of JNK, p38, and ERK resulting in both increased transcriptional activation of the IL-8 promoter and posttranscriptional stabilization of IL-8 mRNA. Because TNFα had been shown to activate ceramide accumulation, and separate studies had linked ceramide with activation of PP2A, we hypothesized the pathway of TNFα-inducing ceramide to activate PP2A comprised an endogenous regulatory pathway. Inhibition of the immediate sphingomyelinase-dependent pathway as well as the de novo synthesis pathway of ceramide production reduced serine/threonine phosphatase activity and augmented IL-8 production. These data suggest that ceramide plays a role in activating PP2A to terminate ongoing IL-8 production. In summary, our data suggest that in respiratory epithelium, TNFα induces ceramide accumulation, resulting in subsequent activation of PP2A, which targets those kinases responsible for transcriptional activation of IL-8.
KW - Airway epithelium
KW - Ceramide
KW - Interleukin-8
KW - Phosphatases
KW - Tumor necrosis factor-α
UR - http://www.scopus.com/inward/record.url?scp=66149185444&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149185444&partnerID=8YFLogxK
U2 - 10.1152/ajplung.90516.2008
DO - 10.1152/ajplung.90516.2008
M3 - Article
C2 - 19286927
AN - SCOPUS:66149185444
SN - 1040-0605
VL - 296
SP - L849-L856
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 5
ER -