Izbicki et al. (1) limited their study mostly to the early response to bleomycin, focusing on the day 14 time point, while our study (2) extended out to day 28. They also used a higher single dose of bleomycin (0.06 mg/mice or 0.06 U/mice, vs 0.02 and 0.05 in our study) to induce the model in their study. At this high dose (0.06 U/mouse) we lost the majority of our animals at day 21, which may account for the focus on day 14 in their study. They did present limited data at day 21 for the IL-4 transgenic mice (IL-4 TG). However, in contrast to what they described in the text, Table I of their paper (1) suggested significant fibrosis equivalent to that in wild-type mice. Nevertheless, the suggestion that overexpression of IL-4 could be protective against early injury agrees with our data showing that IL-4 deficiency caused higher mortality at the high dose of bleomycin (0.05 U/mouse). Nevertheless it would be difficult to directly compare their results using IL-4 TG mice with our studies, which did not use this strain of mouse.
However, based on the use of similar IL-4 knockout mice, our results appear to agree with respect to the suggestion of a more intense acute response to high dose bleomycin in the absence of IL-4. However if these IL-4-deficient mice were allowed to survive the acute phase by using a lower dose of bleomycin, then some protection from fibrosis became evident. Since Izbicki et al. focused on the day 14 time point with an even higher dose of bleomycin (which would have caused significant mortality by day 21), they would have and did miss the protective effects of IL-4 deficiency at the later stages when fibrosis would be maximal. Hence their conclusion based on their limited findings would be appropriate.
When all the available data are taken together, however, it is clear that the role of IL-4 in this model is more complex than their limited study has allowed them to conclude. The extended findings in our study varying the intensity of injury and analysis at later time points suggest that its role is critically time (or disease stage) dependent. Thus it appears to play anti-inflammatory/immunosuppressive roles acutely at doses likely to be present in wild-type mice, but a pro-fibrotic role at later stages if the animals were allowed to survive the initial acute response. This is not unique to IL-4 since IFN-γ also has similar complex albeit opposite roles. Similarly, TNF-α has effects on fibrosis that are dose dependent, with a “normal” dose being profibrotic, while its overexpression appears to attenuate fibrosis (3). Thus it is probably overly simplistic to state that “IL-4 is not a key profibrotic cytokine” in the bleomycin model.
- Copyright © 2003 by The American Association of Immunologists