Soluble calreticulin induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 production by macrophages through mitogen-activated protein kinase (MAPK) and NFκB signaling pathways.

Abstract

We have recently reported that soluble calreticulin (CRT) accumulates in the sera of patients with rheumatoid arthritis or systemic lupus erythematosus. Moreover, following self-oligomerization, soluble recombinant CRT (rCRT) polypeptides exhibit potent immunostimulatory activities including macrophage activation in vitro and antibody induction in vivo. This study was designed to further investigate the underlying molecular mechanisms for soluble CRT-induced macrophage activation. Treatment of murine macrophages with oligomerized rCRT (OrCRT) led to (i) TNF-α and IL-6 transcription and protein expression without affecting intracellular mRNA stability; and (ii) IκBα degradation, NFκB phosphorylation and sustained MAPK phosphorylation in cells. Inhibition of IKK and JNK in macrophages substantially abrogated production of TNF-α and IL-6 induced by OrCRT, while ERK suppression only reduced IL-6 expression in parallel experiments. In vitro, fucoidan, a scavenger receptor A (SRA)-specific ligand, significantly reduced the uptake of FITC-labeled OrCRT by macrophages and subsequent MAPK and NFκB activation, thereby suggesting SRA as one of the potential cell surface receptors for soluble CRT. Together, these data indicate that soluble CRT in oligomerized form could play a pathogenic role in autoimmune diseases through induction of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by macrophages via MAPK-NFκB signaling pathway.

• Authors: Cui-Cui Duo, Fang-Yuan Gong, Xiao-Yan He, Yan-Mei Li, Jun Wang, Jin-Ping Zhang, Xiao-Ming Gao
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 15 Issue 2 Pg. 2916-28 (Feb 20 2014) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 24566135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calreticulin
• Interleukin-6
• NF-kappa B
• Polysaccharides
• Scavenger Receptors, Class A
• Tumor Necrosis Factor-alpha
• fucoidan
• I-kappa B Kinase
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Calreticulin (pharmacology)
• Cells, Cultured
• Female
• I-kappa B Kinase (metabolism)
• Interleukin-6 (genetics, metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Macrophages (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Polysaccharides (pharmacology)
• Scavenger Receptors, Class A (agonists, metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (genetics, metabolism)