Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A.
IL-22 has both proinflammatory and tissue-protective properties depending on the context in which it is expressed. However, the factors that influence the functional outcomes of IL-22 expression remain poorly defined. We demonstrate that after administration of a high dose of bleomycin that induces acute tissue damage and airway inflammation and is lethal to wild-type (WT) mice, Th17 cell-derived IL-22 and IL-17A are expressed in the lung. Bleomycin-induced disease was ameliorated in Il22-/- mice or after anti-IL-22 monoclonal antibody (mAb) treatment of WT mice, indicating a proinflammatory/pathological role for IL-22 in airway inflammation. However, despite increased bleomycin-induced IL-22 production, Il17a-/- mice were protected from airway inflammation, suggesting that IL-17A may regulate the expression and/or proinflammatory properties of IL-22. Consistent with this, IL-17A inhibited IL-22 production by Th17 cells, and exogenous administration of IL-22 could only promote airway inflammation in vivo by acting in synergy with IL-17A. Anti-IL-22 mAb was delivered to Il17a-/- mice and was found to exacerbate bleomycin-induced airway inflammation, indicating that IL-22 is tissue protective in the absence of IL-17A. Finally, in an in vitro culture system, IL-22 administration protected airway epithelial cells from bleomycin-induced apoptosis, and this protection was reversed after coadministration of IL-17A. These data identify that IL-17A can regulate the expression, proinflammatory properties, and tissue-protective functions of IL-22, and indicate that the presence or absence of IL-17A governs the proinflammatory versus tissue-protective properties of IL-22 in a model of airway damage and inflammation.
Sonnenberg
Gregory F
GF
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nair
Meera G
MG
Kirn
Thomas J
TJ
Zaph
Colby
C
Fouser
Lynette A
LA
Artis
David
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D020381:Interleukin-17 / Q000172:deficiency / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000097043:Interleukin-22
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001761:Bleomycin; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22