Advanced glycation end products play major roles in diabetic complications. They act via their receptor RAGE to induce inflammatory genes such as Cycloxygenase-2 (COX-2). We examined the molecular mechanisms by which the RAGE ligand, S100b, induces COX-2 in monocytes. S100b significantly increased COX-2 mRNA accumulation in THP-1 monocytes at two hr via mRNA stability. This was further confirmed by showing that S100b increased stability of luciferase-COX-2 3'UTR mRNA. Chromatin immunoprecipitation and RNA immunoprecipitation revealed that S100b decreased occupancy of the DNA/RNA binding protein, heterogenous nuclear ribonuclear protein K (hnRNP K), at the COX-2 promoter, but simultaneously increased its binding to the COX-2 3'-UTR. S100b treatment promoted the translocation of nuclear hnRNPK to cytoplasm, while a cytoplasmic translocation deficient hnRNP K mutant inhibited S100b induced COX-2 mRNA stability. siRNA mediated specific knockdown of hnRNP K blocked S100b induced COX-2 mRNA stability, while on the other hand, overexpression of hnRNP K increased S100b-induced COX-2 mRNA stability. S100b promoted the release of entrapped COX-2 mRNA from cytoplasmic Processing-bodies, sites of mRNA degradation. Furthermore, S100b significantly down-regulated the expression of a key microRNA, miR-16, which can destabilize COX-2 mRNA by binding to its 3'-UTR. MiR-16 inhibitor oligonucleotides increased, while, conversely, miR-16 mimic oligonucleotides decreased COX-2 mRNA stability in monocytes, further supporting the inhibitory effects of miR-16. Interestingly, hnRNP K knockdown increased miR-16 binding to COX-2 3'-UTR, indicating a cross-talk between them. These new results demonstrate that diabetic stimuli can efficiently stabilize inflammatory genes via opposing actions of key RNA-binding proteins and miRs.