C3A AND C5A ARE CHEMOTAXINS FOR HUMAN MAST-CELLS AND ACT THROUGH DISTINCT RECEPTORS VIA A PERTUSSIS-TOXIN-SENSITIVE SIGNAL-TRANSDUCTION PATHWAY

Mast cells are known to accumulate at sites of inflammation, however, the chemotaxins involved are undefined. Since most natural leukocyte s ecretagogues also induce cell migration, and since the anaphylatoxins C3a and C5a are mast cell secretagogues, we hypothesized that both C3a and C5a are also mast cell chemotaxins. Here we report that C3a and C 5a are, in fact, potent chemotaxins for the human mast cell line HMC-1 . The optimal concentrations, half-maximal effective concentrations (a measure of agonist potency) and the efficacy (response at the optimal concentration) compared with medium control were, for C3a: 10 nM, 0.5 nM, and 256%, respectively; for C5a: 1 nM, 10 pM and 145%. Chemotaxis of HMC-1 cells to both C3a and C5a was blocked by pertussis toxin, su ggesting that G(i)-coupled receptors are involved in signal transducti on. C3a and C5a also induced transient pertussis toxin-inhibitable inc reases in [Ca2+](i) (ED(50) = 1 nM for both) that could be homologousl y but not heterologously desensitized, suggesting that the receptors f or C3a and C5a are distinct. These results make C3a the most effective mast cell chemotaxin identified to date. The chemotactic potency desc ribed here for C3a is also 100- to 1000-fold greater than for all of i ts previously described cellular actions. Direct chemoattraction of ma st cells by C3a and C5a may help explain the rapid accumulation of mas t cells at sites of inflammation.