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Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity.

Junttila IS, Mizukami K, Dickensheets H, Meier-Schellersheim M, Yamane H, Donnelly RP, Paul WE - J. Exp. Med. (2008)

Bottom Line: In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts.The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types.These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. junttilai@niaid.nih.gov

ABSTRACT
Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.

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Estimation of the ability of IL-4 and -13 to assemble receptor complexes. (A) Calculated prediction of the capacity of IL-4 or -13 to assemble receptor complexes in BMDMs. The calculation takes into account three major parameters in receptor chain assemblage namely; the estimated receptor chain expression; the known primary binding efficiency of cytokine/cytokine binding receptor chain and the estimated secondary binding efficiency of cytokine/cytokine binding receptor to the second receptor chain (see text for detailed values). (B) Calculation for predicted assemblages of receptor complexes was performed as in Fig. 7 A, using 2.6-fold more IL-4Rα, 4-fold more γc, and 2.5-fold more IL-13Rα1, based on our results shown in Fig. 6. (C) In NIH3T3, expression of γc is very low or nonexisting (Fig. S3). The calculation was performed as above including only IL-4Rα and IL-13Rα1 expression in the analysis. Fig. S3 is available at http://www.jem.org/cgi/content/full/jem.20080452/DC1.
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fig7: Estimation of the ability of IL-4 and -13 to assemble receptor complexes. (A) Calculated prediction of the capacity of IL-4 or -13 to assemble receptor complexes in BMDMs. The calculation takes into account three major parameters in receptor chain assemblage namely; the estimated receptor chain expression; the known primary binding efficiency of cytokine/cytokine binding receptor chain and the estimated secondary binding efficiency of cytokine/cytokine binding receptor to the second receptor chain (see text for detailed values). (B) Calculation for predicted assemblages of receptor complexes was performed as in Fig. 7 A, using 2.6-fold more IL-4Rα, 4-fold more γc, and 2.5-fold more IL-13Rα1, based on our results shown in Fig. 6. (C) In NIH3T3, expression of γc is very low or nonexisting (Fig. S3). The calculation was performed as above including only IL-4Rα and IL-13Rα1 expression in the analysis. Fig. S3 is available at http://www.jem.org/cgi/content/full/jem.20080452/DC1.

Mentions: Based on our data and the aforementioned binding constants, we wrote a Matlab script to predict the receptor chain assemblage (for details see Materials and methods). For BMDMs (Fig. 7 A), where there are substantial numbers of IL-4Rα chains and of γc chains, but limiting amounts of IL-13Rα1, the prediction is that IL-4 responses are good because large numbers of IL-4–IL-4Rα complexes are formed and there is sufficient γc to drive a reasonable proportion of these into signaling chains. When γc is not present, the concentration of IL-13Rα1 is so low that the number of signaling complexes formed is greatly reduced. In addition, the number of signaling complexes formed is substantially less than the number of IL-13Rα1 chains present because they are recruited to the IL-4–IL-4Rα complex relatively inefficiently. However, the number of signaling chains that can be formed in response to IL-13 can approach the number of IL-13Rα1 chains if sufficient IL-13 is used because the recruitment of IL-4Rα to the IL-13–IL-13Rα1 complex is efficient. Thus, the γc−/− cells respond poorly to IL-4, but can respond quite well to relatively high concentrations of IL-13.


Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity.

Junttila IS, Mizukami K, Dickensheets H, Meier-Schellersheim M, Yamane H, Donnelly RP, Paul WE - J. Exp. Med. (2008)

Estimation of the ability of IL-4 and -13 to assemble receptor complexes. (A) Calculated prediction of the capacity of IL-4 or -13 to assemble receptor complexes in BMDMs. The calculation takes into account three major parameters in receptor chain assemblage namely; the estimated receptor chain expression; the known primary binding efficiency of cytokine/cytokine binding receptor chain and the estimated secondary binding efficiency of cytokine/cytokine binding receptor to the second receptor chain (see text for detailed values). (B) Calculation for predicted assemblages of receptor complexes was performed as in Fig. 7 A, using 2.6-fold more IL-4Rα, 4-fold more γc, and 2.5-fold more IL-13Rα1, based on our results shown in Fig. 6. (C) In NIH3T3, expression of γc is very low or nonexisting (Fig. S3). The calculation was performed as above including only IL-4Rα and IL-13Rα1 expression in the analysis. Fig. S3 is available at http://www.jem.org/cgi/content/full/jem.20080452/DC1.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2571934&req=5

fig7: Estimation of the ability of IL-4 and -13 to assemble receptor complexes. (A) Calculated prediction of the capacity of IL-4 or -13 to assemble receptor complexes in BMDMs. The calculation takes into account three major parameters in receptor chain assemblage namely; the estimated receptor chain expression; the known primary binding efficiency of cytokine/cytokine binding receptor chain and the estimated secondary binding efficiency of cytokine/cytokine binding receptor to the second receptor chain (see text for detailed values). (B) Calculation for predicted assemblages of receptor complexes was performed as in Fig. 7 A, using 2.6-fold more IL-4Rα, 4-fold more γc, and 2.5-fold more IL-13Rα1, based on our results shown in Fig. 6. (C) In NIH3T3, expression of γc is very low or nonexisting (Fig. S3). The calculation was performed as above including only IL-4Rα and IL-13Rα1 expression in the analysis. Fig. S3 is available at http://www.jem.org/cgi/content/full/jem.20080452/DC1.
Mentions: Based on our data and the aforementioned binding constants, we wrote a Matlab script to predict the receptor chain assemblage (for details see Materials and methods). For BMDMs (Fig. 7 A), where there are substantial numbers of IL-4Rα chains and of γc chains, but limiting amounts of IL-13Rα1, the prediction is that IL-4 responses are good because large numbers of IL-4–IL-4Rα complexes are formed and there is sufficient γc to drive a reasonable proportion of these into signaling chains. When γc is not present, the concentration of IL-13Rα1 is so low that the number of signaling complexes formed is greatly reduced. In addition, the number of signaling complexes formed is substantially less than the number of IL-13Rα1 chains present because they are recruited to the IL-4–IL-4Rα complex relatively inefficiently. However, the number of signaling chains that can be formed in response to IL-13 can approach the number of IL-13Rα1 chains if sufficient IL-13 is used because the recruitment of IL-4Rα to the IL-13–IL-13Rα1 complex is efficient. Thus, the γc−/− cells respond poorly to IL-4, but can respond quite well to relatively high concentrations of IL-13.

Bottom Line: In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts.The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types.These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. junttilai@niaid.nih.gov

ABSTRACT
Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.

Show MeSH