Immune Complex Repression of Interferon-gamma Signaling

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Board Number: J-04

Title: Immune Complex Repression of Interferon-gamma Signaling by a

Novel Fc-gamma-Receptor-1 Function

G. H. Boekhoudt , M. R. Frazier-n , G. M. Feldman , DMA, OBP,

OPS, CDER, FDA, Bethesda, MD 20892

Background: Immune complexes (IC) have been implicated in the

initiation and the progression of inflammatory human diseases. The

mechanisms by which the IC and its ligand the Fc-receptor accomplish

these effects are still unknown. In an effort to better understand

the ability of IC to inhibit IFNg-induced activation we concentrated

on dissecting out the point where the signaling pathways of the Fc-

receptor and the IFNg-receptor cross.

Method: Human peripheral blood monocytes that were pretreated with

or without IC followed by stimulation with or without IFNg were used

in numerous in vitro assays including RT-PCR, EMSA,

immunoprecipitation and pull-down. In addition, knockout mice for

the FcRg chain and SHP-1 genes were also studied.

Results: IC inhibits IFNg-induced genes IP-10 and CD64. Data from

the FcR gamma chain knockout mice demonstrates that the gamma chain

is critical to this inhibition. Blocking the FcgR1 with specific

Fab2 fragments mimic the results from the knockout model. Cross-

linking FcgR1/Fab2 complexes reproduced the inhibition of IFNg

induction by IC. The src kinase inhibitor PP2 indicate its

requirement in the function of IC while the data from Motheaten

mouse showed a role for SHP-1 in the repressive function of IC.

Conclusion: The initiation of FcgR1 signaling by IC activates

downstream signaling molecules such as src kinase and SHP-1, which

are required for the inhibitory function of IC. These findings

further elucidate the mechanism by which IC regulates IFNg-

signaling, while adding a level of complexity to the signaling

crosstalk between Fc receptors and by which IFNg is regulated.

Category: J. Biological Endpoints: Microbiology, Virology,

Allergenicity, Biochemistry, Toxicology