Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

Abstract

Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase-2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti-inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX-LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10-1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL-6, TNF-α, peroxisome proliferator-activated receptor (PPAR)-γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex-induced decreases in ATX and adiponectin secretion, but did not reverse Dex-induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex-treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1-phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti-inflammatory effects of Dex through decreased signaling by the ATX-LPA-inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.-Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer.

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

“…Exposure of the tumor and associated fat pad to fractionated RT further enhanced many of these responses, which were accompanied by increased infiltration of CD-45 + leukocytes into the tumor-associated adipose tissue [39].We also reported [41] that an anti-inflammatory glucocorticoid, dexamethasone (DEX), produced a comprehensive suppression of LPA signaling in cultured human adipose tissue by decreasing the expression of ATX and of the LPA 1 and LPA 2 receptors. DEX also increased the expression of lipid phosphate phosphatase-1 (LPP1), an enzyme that degrades extracellular LPA and attenuates its ability to signal through LPA receptors [41]. As expected, these effects were accompanied by a decrease in the production of multiple inflammatory cytokines/chemokines [41].…”

“…We therefore investigated whether DEX could inhibit the RT-induced activation of the ATX-LPA-inflammatory cycle by using a dose of 1 Gy of γ-rays with cultured human adipose tissue as established previously [21]. An optimum concentration of 100 nM DEX [41] attenuated the effects of irradiation in increasing ATX activity in the culture medium ( Figure 1A) and also decreased ATX in the absence of irradiation, as expected [41].…”

“…We demonstrated previously that the anti-inflammatory glucocorticoid, DEX, has a coordinated action in regulating the ATX-LPA-inflammatory cycle [41]. We therefore investigated whether DEX could inhibit the RT-induced activation of the ATX-LPA-inflammatory cycle by using a dose of 1 Gy of γ-rays with cultured human adipose tissue as established previously [21].…”

“…We validated these results by determining the effects of DEX on RT-mediated events in vivo using normal mice and also mice with orthotopic 4T1 breast tumors. Both mouse models were treated daily with 3 mg/kg DEX or vehicle [41] on the day before RT, during the irradiation of a mammary fat pad with 7.5 Gy of X-rays for three consecutive days, and on the day after the completion of RT. DEX treatment did not significantly alter the RT-induced decrease in tumor weight or tumor volume (Meng, G. and Brindley, D. N., University of Alberta, Edmonton, AB, Canada).…”

“…DEX also increased the expression of lipid phosphate phosphatase-1 (LPP1), an enzyme that degrades extracellular LPA and attenuates its ability to signal through LPA receptors [41]. As expected, these effects were accompanied by a decrease in the production of multiple inflammatory cytokines/chemokines [41]. The anti-inflammatory effects of glucocorticoids depend on: (a) binding of glucocorticoid receptors to glucocorticoid-responsive elements, which modify gene expression by inducing the expression of annexin I and MAPK phosphatase-1); (b) indirect effects on gene expression through the interactions of glucocorticoid receptors with transcription factors, including NFκB and activator protein 1; and (c) glucocorticoid receptor-mediated effects on second-messenger cascades including the PI3K-Akt-eNOS pathway [42].…”