Inhibition of p38 MAPK by Glucocorticoids via Induction of MAPK Phosphatase-1 Enhances Nontypeable Haemophilus influenzae-induced Expression of Toll-like Receptor 2

Abstract

Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. We have demonstrated recently that glucocorticoids synergistically enhance nontypeable Haemophilus influenzae (NTHi)-induced expression of Toll-like receptor 2 (TLR2), an important TLR family member that has been shown to play a critical role in host immune and defense response. However, the molecular mechanisms underlying the glucocorticoid-mediated enhancement of TLR2 induction still remain unknown. Here we show that glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAPK phosphatase-1 (MKP-1) that, in turn, leads to dephosphorylation and inactivation of p38 MAPK, the negative regulator for TLR2 expression. Moreover, increased expression of TLR2 in epithelial cells greatly enhances the NTHi-induced expression of several key cytokines, including tumor necrosis factor-␣ and interleukins 1␤ and 8, thereby contributing significantly to host immune and defense response. These studies may bring new insights into the novel role of glucocorticoids in orchestrating and optimizing host immune and defense responses during bacterial infections and enhance our understanding of the signaling mechanisms underlying the glucocorticoid-mediated attenuation of MAPKs.

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

“…p38 MAPK inhibition affected the PDT-induced expression of immune and inflammatory response mediators, such as COX-2 (PTGS2), GM-CSF (granulocyte macrophage colony-stimulating factor; CSF2), interleukin 8 (IL8) and the Toll-like receptor 2, as also reported in previous studies (Hashimoto et al, 2000;Hoffmann et al, 2002;Imasato et al, 2002). Notably, the expression of a number of stress-responsive genes encoding antioxidant and Phase II drug-metabolizing enzymes (Table 2), with an established role in cellular protection following oxidative damage caused by ROS or electrophiles (Lee and Johnson, 2004) was found to be significantly attenuated by PD169316.…”

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.…”

The Tumor Suppressor Cylindromatosis (CYLD) Acts as a Negative Regulator for Toll-like Receptor 2 Signaling via Negative Cross-talk with TRAF6 and TRAF7

“…Cell Culture-Human lung epithelial cell line A549 and human cervix epithelial cell line HeLa were maintained as described (10,33,34). Stable cell lines of HEK293-pcDNA, HEK293-TLR2, and HEK293-TLR4 were kindly provided by Dr. Douglas T. Golenbock (28,29).…”

“…Many cellular stress stimuli can simultaneously activate both NF-B and p38 MAP kinase modules (13,14,(21)(22)(23)(24)(25)(32)(33)(34). Due to this overlap, we explored the possibility that activation of p38 and MKK3/6, its known immediate upstream activators, is involved in the PGN-induced NF-B activation.…”