Characterization of the signal transduction pathway activated in human monocytes and dendritic cells by MPIF-1, a specific ligand for CC chemokine receptor 1
B. Nardelli et al., Characterization of the signal transduction pathway activated in human monocytes and dendritic cells by MPIF-1, a specific ligand for CC chemokine receptor 1, J IMMUNOL, 162(1), 1999, pp. 435-444
The receptor specificity and signal transduction pathway has been identifie
d and characterized for a truncated form of myeloid progenitor inhibitory f
actor-1 (MPIF1(24-99)). MPIF-1 binds specifically to sites, in particular C
CR1, shared with macrophage inflammatory protein-la (MIP-la) on the surface
of human monocytes and dendritic cells, as inferred by its ability to comp
ete for [I-125]MIP-1 alpha, but not for [I-125]MIP-1 beta or [I-125]monocyt
e chemotactic protein-1 (MCP-1) binding to intact cells. Based on calcium f
lux. MPIF-1 is an agonist on CCR1-transfected HEK-293 cells, monocytes, and
dendritic cells, but not on CCR5-, CCR8-, or CX(3)CR1-transfected cells. T
he inhibitory effect of guanosine 5'-O-(3-thio-triphosphate) (GTP-gamma S)
or pertussis toxin pretreatment on MPIF-1 binding and calcium mobilization,
respectively, indicates the involvement of G proteins in the interaction o
f MPIF-1 and its receptor(s). The increase in intracellular free calcium co
ncentration following MPIF-1 treatment is mainly due to the influx of calci
um from an extracellular pool. However, a portion of the intracellular free
calcium concentration is derived from a phospholipase C inhibitor-sensitiv
e intracellular pool. MPIF-1 induces a rapid dose-dependent release of [H-3
]arachidonic acid from monocytes that is dependent on extracellular calcium
and is blocked by phospholipase A(2) (PLA(2)) inhibitors. Furthermore, PLA
(2) activation is shown to be necessary for filamentous actin formation in
monocytes. Thus, the MPH-1 signal transduction pathway appears to include b
inding to CCR1; transduction by G proteins; effector function by phospholip
ase C, protein kinase C, calcium flux, and PLA(2); and cytoskeletal remodel
ing.