The expression of p and

The expression of p38β, γ and δ were also appeared to be higher in specific tissues. p38β expression was abundant in the integrin inhibitor tissue. The elevated level of p38β has been reported in serum of human pancreatic cancer patients and also enhanced bone metastasis in breast cancer (Singh et al., 2012; He et al., 2014). The expression of p38γ was found to be more in skeletal muscle tissues (Cuenda and Rousseau, 2007). Over expressions of p38γ were also detected in colon and breast cancer (Meng and Wu, 2013). In cancers, increased p38δ expression has been detected in human primary cutaneous SCCs, (Haider et al., 2006) and enhanced activation of p38δ has been observed in NSCLC cells lines as well as in HNSCC tumors (Junttila et al., 2007). The role of p38δ was found in cholangiocarcinoma (CC) and Liver malignancy (Tan et al., 2010). P38δ has been reported to regulate HNSCC and CC invasion (Junttila et al., 2007; Tan et al., 2010). Therefore, specifying and to know the contributions of each specific p38 isoform would allow more precise targeting of specific subsets of cancer. Previously our group has reported the elevated p38α protein levels in the serum of HNSCC patients, which decline after radiotherapy (Gill, Mohanti, Ashraf, Singh, and Dey, 2012). In the present study, we first time found significant overexpression of serum p38α, p38β, p38γ, and p38δ in NSCLC patients comparison to normal controls, in which p38α expression was significantly associated with tumor stage and its expression reduced after treatment.
Conflict of interest
Acknowledgements Author acknowledged Indian Council of Medical Research Government of India for the fellowship of Vishal Sahu.
Introduction Neuroinflammation is an important pathological basis and a common feature for the occurrence and development of various central nervous system (CNS) diseases, such as Alzheimer\'s disease (AD), Parkinson\'s disease (PD) and multiple sclerosis (MS) [1]. Microglia is the innate immune cells of the CNS and play a key role in maintaining the homeostasis of brain. Microglia activation is a well-known feature of CNS inflammation. Upon stimulation, microglia can phagocytize and eliminate invasive harmful substances and cell debris, while releasing series of pro-inflammatory factors to protect brain tissues. However, continuously activated microglia produce excessive amount of pro-inflammatory factors that further exacerbate the inflammatory response leading to secondary neuronal death and irreversible damage to nervous system function [2], [3]. There are multiple signaling pathways regulating microglia activation, among which MAPK/NF-κB is one of the most widely studied pathways. Extracellular stimuli, such as lipopolysaccharide (LPS) and high mobility group protein B1 (HMGB1), bind to TLR4, recruit TRAF6 to activate mitogen-activated protein kinases (MAPKs) family, including intracellular signal-regulated kinase 1/2 (ERK1/2), the c-Jun N-terminal (JNK) and p38 MAPK, lead to nuclear factor-κB (NF-κB) activation, and thereby trigger the transcription of a range of pro-inflammatory factors, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), and cycloxygenase-2 (COX-2), to promote microglia activation and immune response [4], [5]. Previous studies have also paid attention to the important linker molecule TRAF6, and demonstrated the important role of the TRAF6/MAPK/NF-κB pathway in regulating neuroinflammation [6], [7]. However, since the signaling pathways governing microglial inflammatory activation is extremely complex, its exact molecular mechanisms are not fully understood. Activating transcription factor 2 (ATF2), also known as cyclic AMP (cAMP) response element (CRE) binding protein 2 (CRE2) and CRE-BP1, is a member of the activator (AP1) transcription factor family, which interacts with other AP1 family members (such as CREB, Fos or Jun) to form homodimers or heterodimers that regulate the transcription of many genes. ATF2 also belongs to the basic-leucine zipper protein (bZIP) family, which comprises N′-terminal zinc finger (ZnF), a transcriptional activation domain (TAD) and a basic leucine zipper (bzip) domain. In the non-activated state, the N′-terminal TAD and C-terminal bZIP DNA binding domains interact and inhibit it\'s activation of transcription. ATF2 can be activated by different extracellular stresses, including ultraviolet (UV), hypoxia, reactive oxygen species (ROS), and inflammatory cytokines, primarily due to the phosphorylation of its two threonine residues (Thr69 and Thr71) catalyzed by JNK/p38 [8], [9], [10]. Many reports indicated that ATF2 participates in cell proliferation, invasion and survival of cancer cells, and plays an important role in tumorigenesis. For example, JNK-dependent phosphorylation of ATF2/c-Jun transcription factor leaded to TGF-β transcription and its signaling activation during oral submucous fibrosis (OSF) lesions [11]. In human glioblastoma (GBM), inhibition of ATF2 suppressed cell proliferation, migration and invasion [12]. Although previous researches mainly focused on the expression and function of ATF2 during tumors development, recent evidence suggested a potential role of ATF2 in inflammation [13]. In ATF2 knockout mice, TNF-α, IL-1β and IL-6 expression were significantly inhibited following LPS stimulation [14]. ATF2 was highly expressed in infiltrating macrophages and inhibited transcription of ATF3, an anti-inflammatory molecule, in M1 macrophages of white adipose tissue [15]. Interestingly, a recent study reported that ATF2 knockdown inhibited IL-6 expression in LPS-treated primary microglia [16]. These evidences implied that ATF2 and its related signaling mechanisms might participate in neuroinflammation. However, the specific role and potential mechanism of ATF2 in CNS inflammation remains unclear.