The role of Poly (ADP-ribose) polymerase in the regulation of innate recognition of immunological receptors expressed on human macrophages.

In order to combat harmful pathogens the innate recognition part of the immune system uses a variety of receptors including CD14, TLR4, TLR2 and SR (MARCO). These receptors are expressed on most human monocytes and macrophages. CD14 recognizes and bind lipopolysaccharide (LPS), the main causative agents of sepsis and endotoxic shock. Signaling from CD14-LPS and TLR4/MD-2 complex activate the nuclear factor kappa B (NF-κB) family of transcription factors and JNK, a member of MAP kinase (MAPK) family. This signaling results in the production of the proinflammatory cytokines such as TNF-α and IL-1β among others. In addition, LPS also activates the DNA-repair and protein modifying enzyme poly (ADP-ribose) polymerase-1 (PARP-1). Consequently, the effect of PJ-34, a potent inhibitor of PARP on PARP-1 activation induced by LPS was studied on THP-1 cells. In response to LPS, PJ-34 reduced the PAR formation and down regulates the expression of CD14, TLR2 and TLR4. However, MARCO expression was up regulated. It was also observed that PJ-34 reduced the production of TNF-α, IL-1β and No in response to LPS. PJ-34 was also involved in a reduction of the activation of NF-κB in response to LPS but, did not have an effect in JNK activation. The physical association of CD14 and MARCO receptors was examined in response to LPS. It was found that PJ-34 reduced the colocalisation of these pair of receptors and regulates their expression at gene level. Furthermore, PJ-34 regulates expression of a number of proteins on the THP-1 cells in response to LPS