Induction of Macrophage-Inflammatory Protein-3α Gene Expression by TNF-Dependent NF-κB Activation

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Abstract
Macrophage-inflammatory protein-3α (MIP-3α), also designated as liver and activation-regulated chemokine (LARC), Exodus, or CCL20, is a recently identified CC chemokine that is expected to play a crucial role in the initiation of immune responses. In this study, we describe that MIP-3α expression is under the direct control of NF-κB, a key transcription factor of immune and inflammatory responses. Overexpression of the p65/RelA subunit of NF-κB significantly increased the MIP-3α mRNA level. MIP-3α transcription was stimulated by TNF, and this stimulation was inhibited by an NF-κB inhibitor, I-κBα superrepressor. Analysis of the human MIP-3α promoter demonstrated a functional NF-κB site responsible for its expression. We also show that MIP-3α expression is induced in LPS-treated mouse livers that were primed with Propionibacterium acnes, which developed massive liver injury with infiltration of inflammatory cells. This induction was fully dependent on the TNF signaling cascade, because it was not observed in the livers of TNFR1-deficient mice. Furthermore, pretreatment with gliotoxin, an inhibitor of NF-κB activity, abrogated the P. acnes/LPS-induced MIP-3α expression of wild-type mice. These results clearly demonstrate that MIP-3α gene expression is dependent on NF-κB activity in vitro, and indicate that the TNFR1-mediated TNF signaling cascade that leads to NF-κB activation plays an essential role in MIP-3α expression in the murine liver injury model.