Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.
BACKGROUND
Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma.


OBJECTIVE
The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10.


METHODS
C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both.


RESULTS
IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity.


CONCLUSIONS
These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium.
K G
KG
Tournoy
J C
JC
Kips
R A
RA
Pauwels
D000276:Adjuvants, Immunologic / Q000633:toxicity; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D007073:Immunoglobulin E / Q000097:blood; D016753:Interleukin-10 / Q000494:pharmacology*; D018664:Interleukin-12 / Q000009:adverse effects / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000939:Epitopes; D016753:Interleukin-10; D018664:Interleukin-12; D007073:Immunoglobulin E