GADD45γ Mediates the Activation of the p38 and JNK MAP Kinase Pathways and Cytokine Production in Effector TH1 Cells

Abstract

The p38 and JNK stress-activated MAPK signal transduction pathways are activated by T cell receptor (TCR) signaling and are required for IFN-gamma production by TH1 effector cells. Here, we show that the expression of GADD45gamma is induced during T cell activation and that the level of expression is higher in TH1 cells than in TH2 cells. TH1 cells from GADD45gamma(-/-) mice are severely compromised in their abilities to activate p38 and JNK in response to TCR signaling, produce much less IFN-gamma upon restimulation, and are deficient in activation-induced cell death (AICD). Additionally, GADD45gamma deficiencies caused reduced contact hypersensitivity in mice. Thus, GADD45gamma mediates activation of the p38 and JNK pathways and effector function of TH1 cells.

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

“…28,42,43 In addition, activation of these pathways induces the activation of the constituent proteins of the activator protein 1 (AP-1) transcription factor complex, such as c-Jun, JunD, and activating transcription factor 2 (ATF2). 44,45 AP-1 is involved in both apoptosis and cell survival.…”

Gadd45 in the response of hematopoietic cells to genotoxic stress

“…Evidence has been obtained that Gadd45 activate p38/JNK signaling and cytokine production in effector T cells (51)(52), whereas Gadd45a activation of p38/JNK in keratinocytes has been implicated in apoptosis (30). The role of the interactions of Gadd45 proteins with MEKK4 in activation of JNK/p38 stress response pathways needs to be established (53)(54).…”

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

“…Only Gadd45a was found to be a p53 target gene (Kastan et al, 1992;Vairapandi et al, 1996). Gadd45b and gadd45g are induced by inflammatory cytokines such as interleukin (IL)-6, IL-12 and IL-18 (Zhang et al, 1999;Lu et al, 2001;Yang et al, 2001). Additionally, gadd45b was induced by tumor necrosis factor (TNF)-a (De Smaele et al, 2001;Amanullah et al, 2003), transforming growth factor (TGF-b) (Selvakumaran et al, 1994;Takekawa et al, 2002;Yoo et al, 2003) and innate immunity signals arising from lipopolysaccharide stimulation (Lang et al, 2002).…”

“…Overall, Gadd45a, Gadd45b and Gadd45g have been implicated in cell cycle arrest (Beadling et al, 1993;Hollander et al, 1999;Wang et al, 1999;Zhang et al, 1999), DNA repair (Smith et al, 1994;Vairapandi et al, 1996), apoptosis (Harkin et al, 1999;Vairapandi et al, 2000;Azam et al, 2001;Takekawa et al, 2002;Yoo et al, 2003), cell survival (Smith et al, 1996;De Smaele et al, 2001;Zazzeroni et al, 2003;Papa et al, 2004;Gupta et al, 2005), genomic stability (Hollander et al, 1999), inflammatory response and innate immunity (Lu et al, 2001;Yang et al, 2001;Lu et al 2004). Gadd45 proteins have been shown to stimulate the p38-c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways in response to stress situations and thereby sensitize cells for growth arrest, apoptosis or survival (Takekawa and Saito, 1998;Harkin et al, 1999;De Smaele et al, 2001;Lu et al, 2001;Hildesheim et al, 2002;Yoo et al, 2003).…”

“…Gadd45 proteins have been shown to stimulate the p38-c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways in response to stress situations and thereby sensitize cells for growth arrest, apoptosis or survival (Takekawa and Saito, 1998;Harkin et al, 1999;De Smaele et al, 2001;Lu et al, 2001;Hildesheim et al, 2002;Yoo et al, 2003). The role of Gadd45 proteins in negative growth regulation is believed to involve direct interaction with various cell cycle components such as proliferating-cell nuclear antigen (PCNA), p21, cdc2 and cyclin B1 (Liebermann and Hoffman (2003) and references therein).…”