IgE-independent interleukin-4 expression and induction of a late phase of leukotriene C4 formation in human blood basophils.
T-helper cells can differentiate into at least two subtypes secreting distinct profiles of cytokines, Th1 and Th2, regulating immunoprotection and different immunopathologies. Interleukin-4 (IL-4) is both the product and the inducer of Th2 cells, raising the question whether IL-4 can be produced in response to antigen-independent stimuli. Here we show that human basophils produce IL-4 on stimulation with IL-3 and C5a or C5adesarg in similar amounts as induced by IgE-receptor-cross-linking. C5a-induced IL-4 production requires the presence of IL-3, with little effect of the sequence of stimuli addition. No "Th1-cytokines" (interferon-gamma and IL-2) and even no "Th2-cytokines" (IL-3, IL-5, IL-10, and granulocyte-macrophage colony-stimulating factor) are produced by basophils in response to either IgE-dependent or IgE-independent activation. The generation of leukotriene C4 (LTC4) is regulated in a similar manner. However, C5a induces a rapid, transient burst of leukotriene formation only if added after IL-3. Interestingly, upon prolonged culture, a late phase of continuous LTC4 production is observed, which also requires two signals (IL-3 and C5a), but rather depends on their continuous presence than on their sequence of action. These data describe an antigen-independent pathway of very restricted IL-4 expression. Thus, basophils must be considered as central immunoregulatory cells of the innate immune system. Furthermore, the results show that LTC4 can also be generated more continuously for many hours, a phenomenon that may be of particular importance in chornic allergic inflammation, such as asthma.
D001491:Basophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015936:Complement C5a / Q000494:pharmacology; D015937:Complement C5a, des-Arginine / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D017997:Leukotriene C4 / Q000096:biosynthesis* / Q000097:blood; D015398:Signal Transduction
D015937:Complement C5a, des-Arginine; D016207:Cytokines; D007377:Interleukin-3; D015847:Interleukin-4; D017997:Leukotriene C4; D007073:Immunoglobulin E; D015936:Complement C5a