Ca. Dahinden et al., MONOCYTE CHEMOTACTIC PROTEIN-3 IS A MOST EFFECTIVE BASOPHIL-ACTIVATING AND EOSINOPHIL-ACTIVATING CHEMOKINE, The Journal of experimental medicine, 179(2), 1994, pp. 751-756
CC chemokines constitute a novel class of cytokines that attract and a
ctivate monocytes and lymphocytes, as well as basophil and eosinophil
leukocytes, with distinct target cell profiles, and are believed to be
involved in the regulation of different types of inflammation. The ac
tion of the recently identified monocyte chemotactic protein 3 (MCP-3)
on human basophil and eosinophil function was studied and compared wi
th that of other CC chemokines. In basophils, MCP-3, MCP-1, RANTES, an
d macrophage inflammatory protein (MIP)-1 alpha all induced cytosolic-
free calcium concentration ([Ca2+]i) changes and, with different effic
acies, chemotaxis (RANTES = MCP-3 >> MCP-1 > MIP-1 alpha), histamine r
elease (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha), and leukotriene C4 for
mation, after IL-3 pretreatment (MCP-1 = MCP-3 >> RANTES > MIP-1 alpha
). Thus, MCP-3 was as effective as MCP-1 as an inducer of mediator rel
ease, and as effective as RANTES as a stimulus of basophil migration.
In contrast to MCP-1, MCP-3 was also a stimulus for eosinophils, and i
nduced [Ca2+](i) changes and chemotaxis as effectively as RANTES, whic
h is the most potent chemotactic cytokine for these cells. Desensitiza
tion of the transient changes in [Ca2+]i was used to assess receptor u
sage. In basophils, stimulation with MCP3 prevented responsiveness to
MCP-1 and RANTES, but not to MIP-1 alpha. No single CC chemokine (acce
pt for MCP-3 itself) affected the response to MCP-3, however, which wa
s prevented only when the cells were prestimulated with both MCP-1 and
RANTES. In eosinophils, by contrast, cross-desensitization between RA
NTES and MCP-3 was obtained. RANTES and to a lesser extent MCP-3 also
desensitized eosinophils toward MIP-1 alpha. The desensitization data
suggest the existence of three chemokine receptors: (a) a MCP-1 recept
or expressed on basophils but not eosinophils that is activated by MCP
-1 and MCP-3; (b) a RANTES receptor in basophils and eosinophils that
is activated by RANTES and MCP-3; and (c) a MIP-1 alpha receptor that
is activated by MIP-1 alpha, RANTES and, more weakly, by MCP-3. This s
tudy shows that MCP-3 combines the properties of RANTES, a powerful ch
emoattractant, and MCP-1, a highly effective stimulus of mediator rele
ase, and thus has a particularly broad range of activities toward both
human basophil and eosinophil leukocytes.