Metallothionein mediates leukocyte chemotaxis.
BACKGROUND
Metallothionein (MT) is a cysteine-rich, metal-binding protein that can be induced by a variety of agents. Modulation of MT levels has also been shown to alter specific immune functions. We have noticed that the MT genes map close to the chemokines Ccl17 and Cx3cl1. Cysteine motifs that characterize these chemokines are also found in the MT sequence suggesting that MT might also act as a chemotactic factor.


RESULTS
In the experiments reported here, we show that immune cells migrate chemotactically in the presence of a gradient of MT. This response can be specifically blocked by two different monoclonal anti-MT antibodies. Exposure of cells to MT also leads to a rapid increase in F-actin content. Incubation of Jurkat T cells with cholera toxin or pertussis toxin completely abrogates the chemotactic response to MT. Thus MT may act via G-protein coupled receptors and through the cyclic AMP signaling pathway to initiate chemotaxis.


CONCLUSIONS
These results suggest that, under inflammatory conditions, metallothionein in the extracellular environment may support the beneficial movement of leukocytes to the site of inflammation. MT may therefore represent a "danger signal"; modifying the character of the immune response when cells sense cellular stress. Elevated metallothionein produced in the context of exposure to environmental toxicants, or as a result of chronic inflammatory disease, may alter the normal chemotactic responses that regulate leukocyte trafficking. Thus, MT synthesis may represent an important factor in immunomodulation that is associated with autoimmune disease and toxicant exposure.
Yin
Xiuyun
X
Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269-3125, USA. xiuyun.yin@uconn.edu
Knecht
David A
DA
Lynes
Michael A
MA
D000199:Actins / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D054414:Chemokine CCL17; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000737:chemistry; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003545:Cysteine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D008668:Metallothionein / Q000037:antagonists & inhibitors / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D011817:Rabbits; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000199:Actins; D000911:Antibodies, Monoclonal; C106230:CCL17 protein, human; C515255:CXCL12 protein, human; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008668:Metallothionein; D003545:Cysteine