Mitogen-activated protein kinase phosphatase-1 expression in macrophages is controlled by lymphocytes during macrophage activation

Abstract

Abstract. The viewpoints on the control of innate immune cells by the adaptive immune system during sepsis remain controversial. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is essential to the negative control of innate immunity and suppresses the activation of macrophages by inhibiting activated mitogen-activated protein kinase (MAPK). The purpose of the current study was to observe inflammatory response and macrophage activation in mice with severe combined immunodeficiency (SCID) with endotoxemia and to determine the role of MKP-1 in the control of macrophage activation by the adaptive immune system. Endotoxemia was induced in wild-type and SCID mice by an intraperitoneal injection of lipopolysaccharide (LPS), and all of the SCID mice died. SCID mice produced more inflammatory cytokines than BALB/c mice systemically and locally. TNF-α mRNA expression was higher and MKP-1 mRNA expression was lower in peritoneal macrophages (PMa) from SCID mice compared to PMa from wild-type mice after and even before LPS injection. Thioglycollate-stimulated PMa from wild-type mice were stimulated with LPS in vitro in the presence or absence of pan-T cells. The levels of TNF-α and IL-6 were higher in the supernatants from PMa cultured alone compared to PMa co-cultured with pan-T cells, and PMa MKP-1 mRNA and protein expression were higher when PMa were co-cultured with pan-T cells. Therefore, pan-T cells can up-regulate MKP-1 expression in macrophages and inhibit the secretion of inflammatory cytokines secretion by macrophages. In SCID mice, lymphocyte deficiency, especially T cell deficiency, causes insufficient MKP-1 expression in macrophages, which can be responsible for the severe inflammation and bad prognosis of septic SCID mice. MKP-1 plays an important role in the control of macrophage activation by the adaptive immune system.

Temporal phenotypic features distinguish polarized macrophagesin vitro

“…The evidence for IL-10 as a M2 marker centers around the larger production of IL-10 from M-CSF cultured macrophages (M2-like) following stimulation with LPS compared to GM-CSF cultured macrophages (M1-like) (46). However, in the absence of exogenously added M-CSF or GM-CSF, other macrophage in vitro systems, RAW264.7 cell line (103) and thioglycollate-elicited peritoneal macrophages (104), also produced IL-10 in response to LPS stimulation. As IL-10 may diminish cytokine expression, this cytokine may play a role in buffering pro-inflammatory responses in the context of M1 macrophage polarization.…”

Diversity and specificity of the mitogen-activated protein kinase phosphatase-1 functions

“…In a model of severe combined immunodeficiency with endotoxemia in mice Luo et al found decreased MKP-1 and increased TNF-α mRNA expression in peritoneal macrophages derived from SCID mice in comparison with cells from wild-type littermates prior to and following treatment with LPS [70]. Interestingly, when thioglycollate-treated macrophages were co-cultured with pan-T-cells, the expression of MKP-1 mRNA and protein increased and the expression levels of TNF-α and IL-6 were reduced as compared with wild-type macrophages.…”