Interferon-gamma as a possible target in chronic asthma.
The role of interferon-gamma (IFN-gamma) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-gamma suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-gamma-producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6-/-mice. Treatment with anti-IFN-gamma decreases the number of IFN-gamma-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-gamma to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-gamma.
Kumar
Rakesh K
RK
Department of Pathology, University of New South Wales, Sydney, Australia. R.Kumar@unsw.edu.au
Webb
Dianne C
DC
Herbert
Cristan
C
Foster
Paul S
PS
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D002908:Chronic Disease; D016207:Cytokines / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects / Q000502:physiology*; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology; D018418:Th2 Cells / Q000187:drug effects / Q000502:physiology
D018926:Anti-Allergic Agents; D016207:Cytokines; D007371:Interferon-gamma