Mactinin, a fragment of cytoskeletal alpha-actinin, is a novel inducer of heat shock protein (Hsp)-90 mediated monocyte activation.
BACKGROUND
Monocytes, their progeny such as dendritic cells and osteoclasts and products including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha and IL-1beta play important roles in cancer, inflammation, immune response and atherosclerosis. We previously showed that mactinin, a degradative fragment of the cytoskeletal protein alpha-actinin, is present at sites of monocytic activation in vivo, has chemotactic activity for monocytes and promotes monocyte/macrophage maturation. We therefore sought to determine the mechanism by which mactinin stimulates monocytes.


RESULTS
Radiolabeled mactinin bound to a heterocomplex on monocytes comprised of at least 3 proteins of molecular weight 88 kD, 79 kD and 68 kD. Affinity purification, mass spectroscopy and Western immunoblotting identified heat shock protein (Hsp)-90 as the 88 kD component of this complex. Hsp90 was responsible for mediating the functional effects of mactinin on monocytes, since Hsp90 inhibitors (geldanamycin and its analogues 17-allylamino-17-demethoxygeldanamycin [17-AAG] and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin [17-DMAG]) almost completely abrogated the stimulatory activity of mactinin on monocytes (production of the pro-inflammatory cytokines IL-1alpha, IL-1beta and TNF-alpha, as well as monocyte chemotaxis).


CONCLUSIONS
Mactinin is a novel inducer of Hsp90 activity on monocytes and may serve to perpetuate and augment monocytic activation, thereby functioning as a "matrikine." Blockage of this function of mactinin may be useful in diseases where monocyte/macrophage activation and/or Hsp90 activity are detrimental.
Luikart
Sharon D
SD
Hematology/Oncology Section (111E), Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. sharon.luikart@va.gov.
Panoskaltsis-Mortari
Angela
A
Hinkel
Timothy
T
Perri
Robert T
RT
Gupta
Kalpna
K
Oegema
Theodore R
TR
Gupta
Pankaj
P
D000185:Actinin / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D053582:Interleukin-1alpha / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018841:HSP90 Heat-Shock Proteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008565:Membrane Proteins; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C485291:mactinin, human; D000185:Actinin