Abstracts (complete list) - Wissenschaft Online

Anke Schütz, Hongqi Lue, Jürgen Bernhagen
ERK1/2-MAPK signaling induced by macrophage migration
inhibitory factor (MIF) is influenced by its CXXC motif
MIF is a pleiotropic inflammatory cytokine that plays a pivotal role in a variety of acute
and chronic inflammatory conditions such as septic shock, rheumatoid arthritis and
atherosclerosis. MIF activates the canonical extracellular signal-regulated mitogenactivated
protein kinase (ERK1/2-MAPK) pathway in a sustained fashion and MIFmediated
ERK signaling has been suggested to contribute to the pro-inflammatory
function of MIF in the above diseases. MIF-induced ERK signaling involves CD74, the
cell surface form of invariant chain, and Src kinase activation, but the structure-function
relationships of MIF underlying its ability to activate MAPK signaling have been
unknown. We recently found that MIF activates transient ERK signaling and observed
that the anti-apoptotic activity of MIF was dependent on its Cys-Ala-Leu-Cys (CXXC)
redox sequence motif (Lue et al., Cell. Signal. 2006; Nguyen et al., J. Immunol. 2003).
Here, we wished to examine the role of CXXC on MIF-mediated ERK1/2 signaling in
fibroblasts. We first compared the effects of recombinant C60SMIF, a mutant in which
the critical Cys60 residue of CXXC is mutated to serine, with the effect of wildtype MIF
on ERK1/2 activity in immortalized and primary MIF -/- -mouse embryonic fibroblasts
(MEFs). Surprisingly, C60SMIF was found to be a potent agonist of the MIF-stimulated
ERK signaling effect. To confirm this observation and to test for autocrine effects,
endogenous C60SMIF, which was derived from the supernatants of stimulated MEFs
isolated from transgenic C60S/C60S-MIF mice (MIF cs/cs ), was analyzed. Compared to
wtMEF supernatants, MIF cs/cs supernatants led to a marked upregulation of phospho-
ERK1/2 levels, confirming the critical role that the CXXC motif appears to have for MIFstimulated
ERK-MAPK signaling.