Introduction:
Inflammatory diseases are being considered a serious issue, for which inhibiting the prolonged and excessive macrophage-regulated inflammatory processes can serve as a considerable therapy [1,2]. The orphan nuclear receptor NR4a1, also known as Nurr7, NGFI, NAK-1, has been recognized as a key regulator in inflammation [2,3]. NR4a1 in all kinds of inflammatory diseases has been investigated, such as atherosclerosis, inflammatory bowel diseases, and rheumatoid arthritis, exerting a protective role against inflammation [4]. Inflammatory stimulation could promote the NR4a1 expression via NF-κB in macrophage [5]. However, NR4a1 exerts the anti-inflammatory effects depending on the negative regulator for NFκB [6-8]. NR4a1-KO macrophage displayed the increased productive in pro-inflammatory cytokines and this up-regulation was decreased by NFκB inhibitor [9,10]. Over-expressed NR4a1 exhibits increased IKK expression,which is a inhibitory role in NFκB signaling[9,10]. NR4a1 can directly have effect on p65 to suppress neuroinflammation [9,10]. NR4a1 is also considered a regulator in metabolism during inflammatory responses of immune cells [11,12]. Despite the several previous study, the understanding of downstream genes of NR4a1 remains lacked [13].
To investigate the functioning mechanism of NR4a1 in macrophage, the GSE681767 were employed for analysis. The GO and KEGG enrichment were conducted in DAVID online database. Protein-protein interaction (PPI) network was mapped by Cytoscape. The results showed that PDE4B and cAMP signaling pathway may play key roles in anti-inflammatory function of NR4a1. PDE4B serves as a selectively hydrolytic enzyme of second signal messenger cyclic adenosine monophosphate(cAMP) [14], of which the deficiency represses activation of nuclear factor kappa-B (NF-κB) in various cell stimulated with lipopolysaccharide(LPS) [15]. cAMP has been proved to play an anti-inflammatory function, employed as a solution of inflammation [14,16]. cAMP-activated PKA can inhibit the NFκB signaling through prohibiting the degradation of IκBα[14,17]. Previous studies have demonstrated the close relation of NR4a1’s anti-inflammatory function with the inhibited NFκB signaling [7,18,19]. Thus, we assumed that NR4a1 may regulates PDE4B expression to exert anti-inflammatory function.