In this report we describe the generation of mice deficient in IL-13Rα2 to define the role of this receptor chain in IL-13 responses. IL-13Rα2 may act to modulate the effects of IL-13 in vivo in various ways. IL-13Rα2 could enhance IL-13 activities by increasing the strength of IL-13 signaling or attenuate IL-13 effects by negative signaling or simply as a molecular decoy. Attenuating roles of IL-13Rα2 could explain the lack of evidence for IL-13 effects on T cells or an enhancing role could explain the effect of IL-13 effect on airways hyperreactivity and eosinophil survival distinct from IL-4.
Interestingly, we find that the absence of IL-13Rα2 correlates with nearly complete loss of serum IL-13 and an increase in tissue IL-13 in IL-13R
mice. The lack of serum IL-13 cannot be explained by a lack of IL-13 production in IL-13R
mice as IL-13 is present in tissues of IL-13R
and is produced by activated IL-13R
immune cells. Serum IL-13Rα2 may act as a reservoir for serum IL-13 and extend IL-13 half-life or may function as a natural antagonist of IL-13 as has been shown for IL-4 receptor (34
). We have previously shown that the administration of IL-13Rα2.Fc is effective as an antagonist of IL-13 in vivo (6
). In addition, increased tissue IL-13 in IL-13R
mice cannot be explained by slightly decreased levels of immune IL-13 production. This suggests that in the liver and lung, IL-13Rα2 acts to decrease tissue cytokine levels, possibly via equilibrium with the serum reservoir. Finally, IL-13 appears to regulate the expression of IL-13Rα2, suggesting that ligand and receptor may cross regulate one another.
We find that serum IgE, IgG2a, IgG2b, and IgA levels are increased in IL-13Rα2−/−
mice. Lai and Mosmann (30
) have shown that the administration of IL-13 in vivo enhances plasma levels of IgG2a and IgG2b and B cell survival in vitro. Concurrent changes in IgE may not have been detected in their studies due to assay sensitivity (30
). Increased serum IgE independent of IL-4 was demonstrated in transgenic mice overexpressing IL-13 (23
). Conversely, Bost et al. (37
) have shown that mice treated with anti–IL-13 during oral immunization have significantly reduced intestinal IgA, serum IgA, and serum IgG. Taken together, these data suggest that IL-13 can enhance IgE, IgG2a, IgG2b, and IgA levels in vivo and are consistent with an enhanced IL-13 response in IL-13Rα2–deficient mice.
Here, we show that IL-13R
mice have increased macrophage progenitors and decreased tissue macrophage NO and IL-12 production. This is similar to previous studies showing that IL-13 administration in vivo affects monocyte/macrophage development and reduces the sensitivity of mice to LPS-induced shock (20
). In addition, the decreased responsiveness of immune cells to LPS in IL-13R
mice, as shown by decreased expression of IL-12, is similar to studies in vivo showing a diminished response to LPS after the administration of IL-13 (20
). Levels of IL-10, TGF-β, and prostaglandin E2 (unpublished data), and IL-4 production are similar from IL-13R
– and IL-13R
–derived macrophages and spleen cells and cannot explain the decreased production of NO in response to LPS and IFN-γ.
Taken together, our studies indicate that overall IL-13Rα2 serves to dampen IL-13–mediated responses in vivo. The absence of this receptor results in decreased responsiveness to LPS, increased levels of bone marrow macrophage progenitors, and enhanced levels of serum IgA, IgE, IgG2a, and IgG2b in wild-type mice. All of these effects are consistent with enhanced IL-13 responses in vivo. This interpretation is also consistent with the enhancement of IL-13–mediated fibrosis observed in Schistosoma mansoni–
). These studies serve to underscore the potent role IL-13 plays in both wild-type mice and in mice undergoing vigorous immune responses to pathogens and the necessity for precise control of IL-13 levels in vivo.