Involvement of tyrosine phosphatase SHP-1 in the regulation of IL-12p40 production in murine splenic macrophages

Abstract

Defects in IL-12p40 production characterize pathological conditions including autoimmunity. SHP-1 null Motheaten (me/me) mice, used as a model, develop autoimmunity due to deregulated production of pro-inflammatory and regulatory cytokines. LPS stimulated me/me splenic macrophages showed significant suppression of IL-12p40 production. Interfering with SHP-1 expression/function in normal splenic macrophages or reconstitution of SHP-1 expression in me/me macrophages affected LPS induced IL-12 production. To understand the involvement of SHP-1 in LPS induced IL-12p40, we investigated the role of signaling pathways. Data revealed roles for calmodulin/calcinuerin pathways as critical components of IL-12p40 production in LPS stimulated splenic macrophages. JNK and P38 MAPK were not involved in IL-12p40 production in murine splenic macrophages, while activation of PI3K or ERK pathways inhibited LPS induced IL-12p40 production, suggesting a negative role of these pathways on calcium induced IL-12p40 gene expression. In addition, IL-12p40 promoter analyses showed alternative binding of calcium activated NFAT, NFkappaB and AP1.