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.