The Role of Mitogen-activated Protein Kinase Phosphatase-1 in the Response of Alveolar Macrophages to Lipopolysaccharide

Abstract

Mitogen-activated protein (MAP) kinases are critical mediators of innate immune responses. In response to lipopolysaccharide (LPS), MAP kinases are rapidly activated and play an important role in the production of proinflammatory cytokines. Although a number of MAP kinase phosphatases (MKPs) have been identified, their roles in the control of cytokine production have not been well defined. In the present report, we investigated the role of MKP-1 in alveolar macrophages stimulated with LPS. We found that LPS triggered transient activation of three MAP kinase subfamilies, ERK, JNK, and p38, in both immortalized and primary murine alveolar macrophages. MKP-1 was rapidly induced by LPS, and its induction correlated with the dephosphorylation of these MAP kinases. Blocking MKP-1 with triptolide prolonged the activities of both JNK and p38 in immortalized alveolar macrophages. Stimulation of primary alveolar macrophages isolated from MKP-1-deficient mice with LPS resulted in a prolonged p38 phosphorylation compared with wild type alveolar macrophages. Accordingly, these MKP-1-deficient alveolar macrophages also mounted a more robust and rapid tumor necrosis factor ␣ production than their wild type counterparts. Adenovirus-mediated MKP-1 overexpression significantly attenuated tumor necrosis factor ␣ production in immortalized alveolar macrophages. Finally, MKP-1 was induced by a group of corticosteroids frequently prescribed for the treatment of inflammatory lung diseases, and the anti-inflammatory potencies of these drugs closely correlated with their abilities to induce MKP-1. Our studies indicated that MKP-1 plays an important role in dampening the inflammatory responses of alveolar macrophages. We speculate that MKP-1 may represent a novel target for therapeutic intervention of inflammatory lung diseases.

Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk

“…Factors that negatively regulate MAP kinase activity, by binding to and dephosphorylating active MAP kinases, form part of the dual specificity MAP kinase phosphatase (MKP) family. Consistent with this notion, several recent investigations have shown that MAP kinase specific phosphatase-1 (MKP-1) deficiency results in enhanced and prolonged p38 and JNK activation (Nimah et al, 2005;Wu and Bennett, 2005;Zhao et al, 2005). MKPs were initially identified as early response genes (Lau and Nathans, 1985;Sun et al, 1993) and are expressed ubiquitously in response to growth factors, stress, or heat shock (Farooq and Zhou, 2004;Chi et al, 2006;Hammer et al, 2006).…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…It is expressed in response to GCs A Clark Anti-inflammatory functions of glucocorticoid-induced genes Page 18 of 53 in a wide variety of cell types including mast cells (Kassel et al, 2001), monocytes or macrophages (Abraham et al, 2006;Aeberli et al, 2006;Bhattacharyya et al, 2007;Chen et al, 2002;Zhao et al, 2005), microglia (Zhou et al, 2007), T lymphocytes , dermal, lung and synovial fibroblasts (Phillips et al, 2006;Toh et al, 2004;Yang et al, 2006), endothelial cells (Furst et al, 2007), osteoblasts (Engelbrecht et al, 2003;Leclerc et al, 2004), keratinocytes (Onda et al, 2006;Stojadinovic et al, 2006), adipocytes (Bazuine et al, 2004), lung epithelial cells (Chivers et al, 2006;Hermoso et al, 2004), airway smooth muscle cells (Issa et al, 2007) and HeLa cells (Imasato et al, 2002;Lasa et al, 2002). Typically expression is quite rapid (within one hour), sustained (up to 24 hours), requires relatively low concentrations of GC, and is blocked by the GR antagonist RU486.…”

“…Anti-inflammatory functions of glucocorticoid-induced genes Page 19 of 53 overexpression of DUSP1 attenuates signaling of the JNK and p38 MAPK pathways and inhibits the expression of several inflammatory genes (Chen et al, 2002;Nimah et al, 2005;Zhao et al, 2005).…”

Anionic Pulmonary Surfactant Phospholipids Inhibit Inflammatory Responses from Alveolar Macrophages and U937 Cells by Binding the Lipopolysaccharide-interacting Proteins CD14 and MD-2

“…Treatment of cells with POPG in addition to LPS eliminated the phosphorylation of p38, p42 ERK, JNK, and IB␣ and also abrogated the reduction in the steady state levels of IB␣. In addition to inducing phosphorylation of MAPKs and IB␣, LPS induced synthesis of MKP-1 that functions to turn off MAPKs signaling (42,43). The POPG treatment blocked the synthesis of new MKP-1, indicating that the lipid is likely to act upstream of MAPK activation rather than downstream of the process by induction of MKP-1.…”