Regulation of constitutive and microbial pathogen-induced human macrophage migration inhibitory factor (MIF) gene expression

Eur J Immunol. 2007 Dec;37(12):3509-21. doi: 10.1002/eji.200737357.


The cytokine macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity, inflammation and oncogenesis. However, four decades after its identification, the molecular mechanism(s) regulating the expression of the MIF gene remain largely unknown. Analyses of human monocytic (THP-1), epithelial (HeLa and A549) and keratinocytic (HaCat) cells transfected with wild-type, truncated and mutated MIF promoter reporter constructs, and electrophoretic mobility shift assay, chromatin immunoprecipitation, and siRNA inhibition indicated that the transcription factors specificity protein (Sp)1 and cAMP response element-binding protein (CREB) are critical positive regulators of constitutive human MIF gene expression. Albeit located in a cytosine guanine dinucleotide island, the MIF gene was found to be hypomethylated, an observation consistent with high baseline transcriptional activity. Moreover, stimulation of THP-1 cells and of peripheral blood mononuclear cells with microbial products up-regulated phosphorylated Sp1 nuclear content, Sp1 DNA-binding activity, MIF promoter activity and MIF mRNA levels in a MEK1/2-, Sp1-dependent manner. Taken together with previous observations of an important role for MIF in pro-inflammatory macrophage responses, these present findings suggest a key role for Sp1 and CREB in transcriptional regulation of MIF gene expression and MIF-dependent host antimicrobial innate immune defense.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aquaporins / biosynthesis
  • Aquaporins / genetics*
  • Base Sequence
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • DNA / metabolism
  • DNA Methylation
  • Escherichia coli
  • Eye Proteins / biosynthesis
  • Eye Proteins / genetics*
  • Gene Expression Regulation* / drug effects
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / physiology*
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics*
  • Molecular Sequence Data
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Neisseria meningitidis
  • Promoter Regions, Genetic
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Sequence Deletion
  • Sp1 Transcription Factor / physiology*
  • Streptococcus pneumoniae
  • Transcription, Genetic / drug effects


  • Aquaporins
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Eye Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Sp1 Transcription Factor
  • aquaporin 0
  • DNA