Activation of the Human RANTES Gene Promoter in a Macrophage Cell Line by Lipopolysaccharide Is Dependent on Stress-Activated Protein Kinases and the IκB Kinase Cascade: Implications for Exacerbation of Allergic Inflammation by Environmental Pollutants

Macrophages are targeted by environmental pollutants and play a role in allergic inflammation. We explored the molecular basis for induction of RANTES (regulated upon activation, normal T-cells expressed and secreted) mRNA by lipopolysaccharide (LPS) and the redox-active quinone,tert-butylhydroxyquinone (tBHQ). We demonstrate that transcriptional activation of the human RANTES promoter by LPS is dependent on specific AP-1 and NF-κB response elements, which are regulated by c-Jun N-terminal kinase (JNK) and NF-κB kinase cascades, respectively. The transcriptional activation of the TRE3/4 site is mediated through the transcriptional activation of c-Jun by JNK. A c-Jun mutant which lacks a transcriptional activation domain interfered in the activation of the RANTES promoter. Similarly, kinase-inactive NF-κB inducing kinase interfered in the activation of the RANTES promoter. While activation of the RANTES promoter could also be blocked by the downstream kinase-inactive IκB kinases, only IKKα appears to be LPS-inducible. tBHQ also exerted subtle effects on the human RANTES promoter and induced mRNA expression in parallel with generating NF-κB shift complexes.