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 secretagogues 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 C5a 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, suggesting that Gi-coupled receptors are involved in signal transduction. C3a and C5a also induced transient pertussis toxin-inhibitable increases in [Ca2+]i (ED50 = 1 nM for both) that could be homologously but not heterologously desensitized, suggesting that the receptors for C3a and C5a are distinct. These results make C3a the most effective mast cell chemotaxin identified to date. The chemotactic potency described here for C3a is also 100- to 1000-fold greater than for all of its previously described cellular actions. Direct chemoattraction of mast cells by C3a and C5a may help explain the rapid accumulation of mast cells at sites of inflammation.
Nilsson
G
G
Department of Pathology, University Hospital, University of Uppsala, Sweden.
Johnell
M
M
Hammer
C H
CH
Tiffany
H L
HL
Nilsson
K
K
Metcalfe
D D
DD
Siegbahn
A
A
Murphy
P M
PM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology*; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015926:Complement C3a / Q000494:pharmacology*; D015936:Complement C5a / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008407:Mast Cells / Q000187:drug effects*; D008565:Membrane Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D037342:Pertussis Toxin; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D015703:Antigens, CD; D002630:Chemotactic Factors; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D010566:Virulence Factors, Bordetella; C085567:complement C3a receptor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015926:Complement C3a; D015936:Complement C5a; D000255:Adenosine Triphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins