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-kappa B response elements, which are regulated by c-Jun N-terminal kinase (JNK) and NF-kappa B 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-kappa B 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 I kappa B kinases, only IKK alpha appears to be LPS-inducible. tBHQ also exerted subtle effects on the human RANTES promoter and induced mRNA expression in parallel with generating NF-kappa B shift complexes. (C) 1999 Academic Press.