LPS‐induced chemokine expression in both MyD88‐dependent and ‐independent manners is regulated by Cot/Tpl2‐ERK axis in macrophages

Abstract

Edited by Masayuki MiyasakaKeywords: Macrophage Chemokine LPS Cot/Tpl2 ERK a b s t r a c t LPS signaling is mediated through MyD88-dependent and -independent pathways, activating NF-jB, MAP kinases and IRF3. Cot/Tpl2 is an essential upstream kinase in LPS-mediated activation of ERKs. Here we explore the roles of MyD88 and Cot/Tpl2 in LPS-induced chemokine expression by studying myd88 À/À and cot/tpl2 À/À macrophages. Among the nine LPS-responsive chemokines examined, mRNA induction of ccl5, cxcl10, and cxcl13 is mediated through the MyD88-independent pathway. Notably, Cot/Tpl2-ERK signaling axis exerts negative effects on the expression of these three chemokines. In contrast, LPS-induced gene expression of ccl2, ccl7, cxcl2, cxcl3, ccl8, and cxcl9 is mediated in the MyD88-dependent manner. The Cot/Tpl2-ERK axis promotes the expression of the first four and inhibits the expression of the latter two. Thus, LPS induces expression of multiple chemokines through various signaling pathways in macrophages.

Tumor Progression Locus 2 (Tpl2) Kinase Promotes Chemokine Receptor Expression and Macrophage Migration during Acute Inflammation

“…Consistent with previous reports, Fos, IL-1␤, and the chemokines CCL2, CCL7, and CXCL3 were reduced in the absence of Tpl2, whereas IL-12p40 (IL-12B) and IFN␤ expression were increased (Fig. 1A) (26,(32)(33)(34). These findings served to verify the microarray results.…”

“…4). In this regard, Bandow et al (32) have shown previously that the LPS-induced expression of the CCR1/CCR5 specific chemokine ligand CCL5 (RANTES), was increased in tpl2 Ϫ/Ϫ macrophages. We also observed a timedependent increase in CCL5 expression levels in tpl2 Ϫ/Ϫ macrophages (data not shown).…”

“…First, Soria-Castro et al (31) demonstrated that neutrophil chemotaxis toward zymosan in vivo was impaired in tpl2 Ϫ/Ϫ mice. Bandow et al (32) subsequently described that LPS-induced chemokine ligand expression was regulated by the Cot/Tpl2-ERK axis in macrophages. Although these studies highlight the role of Tpl2 in regulating chemokine expression in inflamed tissues and macrophages, they do not address whether Tpl2 may also regulate chemokine receptor expression and whether this regulation impacts overall macrophage migration in vivo.…”

Low Intensity Pulsed Ultrasound (LIPUS) Influences the Multilineage Differentiation of Mesenchymal Stem and Progenitor Cell Lines through ROCK-Cot/Tpl2-MEK-ERK Signaling Pathway

“…We examined the possible involvement of Cot/Tpl2, an essential upstream kinase for the LPS-induced ERK phosphorylation in a variety of cell types (17)(18)(19)(20)(21). We found that Cot/Tpl2 was rapidly phosphorylated in LIPUS-stimulated 3T3-L1, MC3T3-E1, and ST2 cells (Fig.…”

Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide

“…These signalling pathways produce pro-inflammatory cytokines via p38, JNKs, ERKs, and IKK protein kinase cascades, leading to activation of transcription factors such as NF-κB AP-1 and IRF3, which promote expression of cytokine-encoding genes. Therefore, LPS-mediated production of cytokines (IL-6, TNF-α, IL-1β, MCP-1, IFN-β) in RAW264.7 cells occurs via PI3K/Akt, MAPK, JAK/STAT pathways [37-42]. …”