The role of interleukin-33 in chronic allergic conjunctivitis.
OBJECTIVE
The authors discovered a genetic association between the ST2L gene and atopy. The ST2L gene encodes a membrane-bound functional marker for Th2 cells. Recently, a novel Th2 cytokine, interleukin-33 (IL-33), was discovered to be a specific ligand for ST2L. The authors investigated the role of IL-33 in chronic allergic conjunctivitis.


METHODS
Immunohistochemical analysis was carried out using giant papillae samples obtained from patients with atopic keratoconjunctivitis. The authors used proinflammatory stimuli to clarify IL-33 mRNA/protein-inducing signals with cultured human conjunctival epithelial cells, fibroblasts, human umbilical vascular endothelial cells, and mast cells. These cells were also used to examine the expression of ST2L (IL-33R). Finally, cultured mast cells were stimulated with recombinant IL-33 (rIL-33) to examine the downstream signals.


RESULTS
The authors found IL-33 protein expression in human vascular endothelial cells in the giant papillae and in the control conjunctivae. IL-33 expression was also observed in conjunctival epithelium of the giant papillae but not in the control conjunctivae. IL-1 beta stimulation upregulated IL-33 mRNA expression in conjunctival fibroblasts. The authors also confirmed mature IL-33 protein expression in ocular resident cells by Western blot analysis. Preferential ST2L expression was observed in human mast cells, and phosphorylation of p38 MAPK and IL-13 mRNA induction was observed in human cultured mast cells after rIL-33 stimulation. Phosphorylation of p38 MAPK was inhibited by soluble ST2 protein.


CONCLUSIONS
The IL-33-ST2 signaling cascade plays some roles in the pathophysiology of chronic allergic conjunctivitis through the activation of mast cells.
Matsuda
Akira
A
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. akimatsu@koto.kpu-m.ac.jp
Okayama
Yoshimichi
Y
Terai
Noriko
N
Yokoi
Norihiko
N
Ebihara
Nobuyuki
N
Tanioka
Hidetoshi
H
Kawasaki
Satoshi
S
Inatomi
Tsutomu
T
Katoh
Norito
N
Ueda
Eiichiro
E
Hamuro
Junji
J
Murakami
Akira
A
Kinoshita
Shigeru
S
D015153:Blotting, Western; D002478:Cells, Cultured; D002908:Chronic Disease; D003228:Conjunctiva / Q000187:drug effects / Q000378:metabolism; D003233:Conjunctivitis, Allergic / Q000378:metabolism* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053583:Interleukin-1beta / Q000494:pharmacology; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface