Aberrant stress-induced Hsp70 expression in immune cells in multiple sclerosis.
Heat shock protein 70 (Hsp70), a prominent member of the heat shock protein family, is a stress-induced chaperone, contributing to the "protein triage" mechanism. However, we and others have previously shown that chaperonin activity of Hsp70 also promotes immune recognition of protein/peptide antigens, including myelin autoantigens. Hsp70 has been strikingly elevated in multiple sclerosis (MS) lesions. In a search for the mechanism of Hsp70 up-regulation in MS, we analyzed Hsp70 expression in peripheral blood mononuclear cells (PBMCs) from MS patients (n = 49), healthy controls (n = 40), and patients with rheumatoid arthritis, (RA; n = 13). Hsp70 was detected by Western blot, and Hsp70 levels were quantified by ELISA. We found that Hsp70 was expressed at low levels in ex vivo PBMCs. However, after heat shock, Hsp70 was up-regulated significantly more (up to sixfold) in MS patients compared with healthy controls. This significant overproduction of Hsp70 was also seen following another stress condition, LPS stimulation. Hsp70 is a product of several independent genes, and we found the HSPA1B gene product to be the major form responsible for Hsp70 protein overexpression in PBMCs. Hsp70 overexpression was preceded by increased nuclear presence of heat shock factor 1 (HSF1). HSF1 activation depends on phosphorylation, and we found that inhibition of the A group of protein kinase C isoenzymes significantly reduced inducible Hsp70 production. These results indicate that immune cells from MS patients are more prone to Hsp70 induction under stress conditions, suggesting a possible link between Hsp70 overexpression and development of autoimmunity.
Cwiklinska
Hanna
H
Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Lodz, Poland.
Mycko
Marcin P
MP
Szymanska
Bozena
B
Matysiak
Mariola
M
Selmaj
Krzysztof W
KW
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology*
D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger