Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway.
Mast cells are exposed to an oxidative environment in the course of allergic and inflammatory reactions. We have examined the effects of H(2)O(2) stimulation in a primary rat basophilic leukemia cell line (RBL-2H3) and compared with IgE-dependent stimulation. Like IgE stimulation, H(2)O(2) up-regulates IL-4 and IL-6 gene expression and cytokine secretion, shows a little effect on IL-5 but does not induce IL-10 gene expression. Simultaneous H(2)O(2) treatment and FcepsilonRI triggering of mast cells has additive effects on IL-4 expression. In addition, we show that both stimuli induce the nuclear translocation of APE/Ref-1, a bifunctional enzyme that stimulates the DNA-binding activity of several transcription factors through the reduction of highly reactive cysteines. Conditional inactivation of APE/Ref-1 expression abolishes H(2)O(2)-induced IL-4 and IL-6 gene expression but does not affect that induced by FcepsilonRI stimulation. Our findings indicate that oxidative stress activates the gene expression of a specific cytokine pattern in mast cells through an APE/Ref-1-dependent pathway, which is distinct from the one that is activated by FcepsilonRI stimulation. Nonetheless, H(2)O(2) and FcepsilonRI signalings are additive in augmenting IL-4 production. Most importantly, oxidative stress can induce a pro-type 2 inflammatory response from mast cells that is independent of FcepsilonRI stimulation.
Frossi
Barbara
B
Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, Udine, Italy.
De Carli
Marco
M
Daniel
Kenn Curt
KC
Rivera
Juan
J
Pucillo
Carlo
C
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D019757:Carbon-Oxygen Lyases / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D017455:Receptors, IgE; D015847:Interleukin-4; D006861:Hydrogen Peroxide; D019757:Carbon-Oxygen Lyases; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase