Abstracts (complete list) - Wissenschaft Online

Stephanie Konrad, Linda Engling, Reinhold E. Schmidt, J. Engelbert Gessner
INVERSE REGULATION OF THE MURINE FcγRIIB AND FcγRIII
GENE EXPRESSION BY C5a IS MEDIATED THROUGH DISTINCT
DNA-RESPONSE ELEMENTS
The crucial role of Fcγ receptors (FcR) in antibody-mediated autoimmune diseases is
reflected in gene deletion studies in mice. Like other immune regulatory receptor pairs,
the FcR system is constituted by a balanced action of activating and inhibitory receptors
that bind immune-complexed IgG with same affinity. Analyses of animal models have
shown that the inhibitory FcγRIIB can suppress antibody-mediated autoimmunity,
whereas activating FcR - FcγRIII promote disease development. Although in vivo
analysis of alveolar and peritoneal macrophages in mice shown an indispensable role of
the complement component C5a in the regulation of FcR and the sensing of FcRdependent
effector cell responses but the molecular mechanism is still unclear. To
understand the C5a-mediated regulatory mechanisms of FcR expression, we cloned
both the murine FcγRIII and FcγRIIB genes and demonstrated that inverse gene
regulation of FcγRIII and FcγRIIB is mediated by functionally distinct cis-active DNA
promoter elements in their 5´-end regions, which show a similar sequence motive.
Deletion analysis defined a contribution of the 48-bp(–808/–760) region of the FcγRIII
promoter and the promoter-associated intronic 42-bp(+442/+484) region of FcγRIIB in
confering C5a responsiveness of FcγRIII induction versus FcγRIIB suppression. The
importance of Gi, PI3K and Akt signaling molecules in the C5aR activation pathway that
differentially control FcR reporter gene activities was further established by
pharmacological inhibition studies in transfected MH-S and RAW 264.7 macrophage cell
lines. This study provides insight into the transcriptional regulation of FcR,
demonstrating the importance of functional different DNA elements in the murine
FcγRIIB and FcγRIII genes.
Research supported by SFB587 to JE.G.