Cyclophilin C-associated protein regulation of phagocytic functions via NFAT activation in macrophages.

Experimental cerebral ischemia has been reportedly alleviated by the immunosuppressive agent cyclosporin A (CsA). Cyclophilin C-associated protein (CyCAP) was proposed to be an endogenous equivalent of CsA; CsA- and CyCAP-targeting protein cyclophilin C have attracted extensive attention regarding their ischemia-alleviating mechanisms. In this study we have introduced the specific CyCAP antibody for evaluating its distribution in the rat ischemic brain after middle cerebral artery occlusion. During the recovery of cerebral ischemia in rats, CyCAP was highly expressed in the activated microglia/macrophages in the ischemic lesion. However, it remains unknown what roles CyCAP plays in the activation of macrophage phagocytosis. Thus, we studied CyCAP function using a RAW264.7 macrophage cell line. When we expressed CyCAP-GFP and cyclophilin C-FLAG in RAW264.7 cells, we found that CyCAP and cyclophilin C make a complex, which is competitively inhibited by CsA. Consistently, in immunoprecipitates by anti-calcineurin antibody, cyclophilin C and CyCAP were detected, and CyCAP pulled down NFATc1, suggesting that both CyCAP and cyclophilin C form a complex with calcineurin and NFATc1. When CyCAP was adenovirally overexpressed in RAW cells, NFAT staining increased over the nucleus. Furthermore, calcineurin and IL-2 were increased with time. Thus, CyCAP appears to control macrophage functions by activating NFAT and the resultant IL-2 production. With a protein phosphatase inhibitor PhoSTOP, NFAT was localized more to the cytoplasm, and phagocytosis was decreased strikingly. Thus, we suggest that in a CyCAP-cyclophilin C pathway for macrophage activation, calcineurin phosphatase activity is essential for the phagocytosis activity via dephosphorylation of NFATc1.
AuthorsRei Yamaguchi, Masahiro Hosaka, Seiji Torii, Ni Hou, Nobuhito Saito, Yuhei Yoshimoto, Hideaki Imai, Toshiyuki Takeuchi
JournalBrain research (Brain Res) Vol. 1397 Pg. 55-65 (Jun 23 2011) ISSN: 1872-6240 [Electronic] Netherlands
PMID21435337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier B.V. All rights reserved.
Chemical References
  • Carrier Proteins
  • Cyclophilin C-associated protein, rat
  • NFATC Transcription Factors
  • Nerve Tissue Proteins
  • Cyclosporine
  • Phosphoric Monoester Hydrolases
  • Calcineurin
  • Cyclophilins
  • cyclophilin C
  • Calcium
  • Adenoviridae (genetics)
  • Animals
  • Binding, Competitive (drug effects)
  • Brain Ischemia (pathology)
  • Calcineurin (metabolism)
  • Calcium (physiology)
  • Carrier Proteins (biosynthesis, genetics, physiology)
  • Cell Line
  • Cyclophilins (physiology)
  • Cyclosporine (metabolism)
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery (pathology)
  • Macrophage Activation (genetics, physiology)
  • Macrophages (physiology)
  • Male
  • Mice
  • NFATC Transcription Factors (genetics, physiology)
  • Nerve Tissue Proteins (biosynthesis, genetics, physiology)
  • Phagocytosis (genetics, physiology)
  • Phosphoric Monoester Hydrolases (antagonists & inhibitors)
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Subcellular Fractions (metabolism)
  • Up-Regulation (physiology)

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