Proposed model of S100A8/9 induction.

Abstract

PTGIR and PTGER4 are activated by their ligands (PGI2 and PGE2 respectively) turning on the AC which converts ATP into cAMP; cAMP activates PKA which in turn triggers STAT3 by phosphorylation. STAT3 binds to the promoters (S9 Fig) of S100A8 and S100A9 inducing their expression. TLR4 and when activated by its ligand LPS, activates the JAK2-STAT3 pathway which induces the expression of S100A8/9 and inhibits NF-kB. We have shown the induction of S100A8/9 genes in THP-1 activated by LPS (Fig 5). ZBTB40 could potentially bind directly to the S100A8/9 promoters inducing their expression and/or to the PLA2G1B promoter (by Encode) activating its expression. PLA2G1B encodes an enzyme that initiates the PG synthesis including PGI2 and PGE2 which bind PTGIR and PTGER4 respectively, inducing S100A8/S100A9 (see above). Based on RNAseq data, expression of NFKB1 in THP-1 induces the expression of EBI3 (one of the top 5 HITS) (S3A Table) most likely via direct binding to the EBI3 promoter by RELB subunit. EBI3 encodes the interleukine-27 subunit beta, which can bind to IL27R and activate JAK/STAT3 pathway [55,56]. In addition, NFKB1 induces the expression of PTGIR ((S10 Fig). RELB binds directly to PTGIR promoter (by Encode).</p