Granzyme B, a novel mediator of allergic inflammation: its induction and release in blood basophils and human asthma.
Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.
Tschopp
Cornelia M
CM
Institute of Immunology, Inselspital, University Hospital Bern, Inselspital, CH-3010 Bern, Switzerland.
Spiegl
Nicole
N
Didichenko
Svetlana
S
Lutmann
Werner
W
Julius
Peter
P
Virchow
J Christian
JC
Hack
C Erik
CE
Dahinden
Clemens A
CA
D000911:Antibodies, Monoclonal / Q000737:chemistry; D001249:Asthma / Q000097:blood* / Q000378:metabolism; D001491:Basophils / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D015936:Complement C5a / Q000737:chemistry; D053804:Granzymes; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018793:Interleukin-13; D007377:Interleukin-3; D017997:Leukotriene C4; D015936:Complement C5a; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases