An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13- induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors

doi:10.1084/jem.178.6.2213

This Article

	Full Text (PDF, 536K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Aversa, G.
	Articles by de Vries, J. E.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Aversa, G.
	Articles by de Vries, J. E.


Social Bookmarking

	What's this?

ARTICLES

An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13- induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors

G Aversa, J Punnonen, BG Cocks, R de Waal Malefyt, F Vega Jr, SM Zurawski, G Zurawski and JE de Vries
Human Immunology Department, DNAX Research Institute, Palo Alto, California 94304-1104.

Interleukin 4 (IL-4) and IL-13 share many biological functions. Both cytokines promote growth of activated human B cells and induce naive human surface immunoglobulin D+ (sIgD+) B cells to produce IgG4 and IgE. Here we show that a mutant form of human IL-4, in which the tyrosine residue at position 124 is replaced by aspartic acid (hIL- 4.Y124D), specifically blocks IL-4 and IL-13-induced proliferation of B cells costimulated by anti-CD40 mAbs in a dose-dependent fashion. A mouse mutant IL-4 protein (mIL-4.Y119D), which antagonizes the biological activity of mouse IL-4, was ineffective. In addition, hIL- 4.Y124D, at concentrations of up to 40 nM, did not affect IL-2-induced B cell proliferation. hIL-4.Y124D did not have detectable agonistic activity in these B cell proliferation assays. Interestingly, hIL- 4.Y124D also strongly inhibited both IL-4 or IL-13-induced IgG4 and IgE synthesis in cultures of peripheral blood mononuclear cells, or highly purified sIgD+ B cells cultured in the presence of anti-CD40 mAbs. IL-4 and IL-13-induced IgE responses were inhibited > 95% at a approximately 50- or approximately 20-fold excess of hIL-4.Y124D, respectively, despite the fact that the IL-4 mutant protein had a weak agonistic activity. This agonistic activity was 1.6 +/- 1.9% (n = 4) of the maximal IgE responses induced by saturating concentrations of IL-4. Taken together, these data indicate that there are commonalities between the IL-4 and IL-13 receptor. In addition, since hIL-4.Y124D inhibited both IL-4 and IL-13-induced IgE synthesis, it is likely that antagonistic mutant IL-4 proteins may have potential clinical use in the treatment of IgE-mediated allergic diseases.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

Francipane, M. G., Perez Alea, M., Lombardo, Y., Todaro, M., Medema, J.P., Stassi, G. (2008). Crucial Role of Interleukin-4 in the Survival of Colon Cancer Stem Cells. Cancer Res. 68: 4022-4025 [Abstract] [Full Text]
Kioi, M., Seetharam, S., Puri, R. K. (2006). N-linked glycosylation of IL-13R{alpha}2 is essential for optimal IL-13 inhibitory activity. FASEB J. 20: 2378-2380 [Abstract] [Full Text]
Ahn, J. S., Agrawal, B. (2005). IL-4 is more effective than IL-13 for in vitro differentiation of dendritic cells from peripheral blood mononuclear cells. Int Immunol 17: 1337-1346 [Abstract] [Full Text]
Boyce, J. A., Austen, K. F. (2005). No audible wheezing: nuggets and conundrums from mouse asthma models. JEM 201: 1869-1873 [Abstract] [Full Text]
Satoguina, J. S., Weyand, E., Larbi, J., Hoerauf, A. (2005). T Regulatory-1 Cells Induce IgG4 Production by B Cells: Role of IL-10. J. Immunol. 174: 4718-4726 [Abstract] [Full Text]
McKenzie, A. N.J., Fallon, P. G. (2003). Decoy Receptors in the Regulation of T Helper Cell Type 2 Responses. JEM 197: 675-679 [Full Text]
Ozaki, K., Leonard, W. J. (2002). Cytokine and Cytokine Receptor Pleiotropy and Redundancy. J. Biol. Chem. 277: 29355-29358 [Full Text]
Tomkinson, A., Duez, C., Cieslewicz, G., Pratt, J. C., Joetham, A., Shanafelt, M.-C., Gundel, R., Gelfand, E. W. (2001). A Murine IL-4 Receptor Antagonist That Inhibits IL-4- and IL-13-Induced Responses Prevents Antigen-Induced Airway Eosinophilia and Airway Hyperresponsiveness. J. Immunol. 166: 5792-5800 [Abstract] [Full Text]
Brutsche, M. H., Brutsche, I. C., Wood, P., Mogulkoc, N., Custovic, A., Egan, J., Woodcock, A. (2001). B-cell isotype control in atopy and asthma assessed with cDNA array technology. Am. J. Physiol. Lung Cell. Mol. Physiol. 280: L627-L637 [Abstract] [Full Text]
Kips, J.C., Tournoy, K.G., Pauwels, R.A. (2001). New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J 17: 499-506 [Abstract] [Full Text]
Ford, D., Sheehan, C., Girasole, C., Priester, R., Kouttab, N., Tigges, J., King, T. C., Luciani, A., Morgan, J. W., Maizel, A. L. (1999). The Human B Cell Response to IL-13 Is Dependent on Cellular Phenotype as Well as Mode of Activation. J. Immunol. 163: 3185-3193 [Abstract] [Full Text]
Chung, K F, Barnes, P J (1999). Cytokines in asthma. Thorax 54: 825-857 [Full Text]
Striz, I., Mio, T., Adachi, Y., Heires, P., Robbins, R. A., Spurzem, J. R., Illig, M. J., Romberger, D. J., Rennard, S. I. (1999). IL-4 induces ICAM-1 expression in human bronchial epithelial cells and potentiates TNF-alpha. Am. J. Physiol. Lung Cell. Mol. Physiol. 277: L58-L64 [Abstract] [Full Text]
Wright, K., Kolios, G., Westwick, J., Ward, S. G. (1999). Cytokine-induced Apoptosis in Epithelial HT-29 Cells Is Independent of Nitric Oxide Formation. EVIDENCE FOR AN INTERLEUKIN-13-DRIVEN PHOSPHATIDYLINOSITOL 3-KINASE-DEPENDENT SURVIVAL MECHANISM. J. Biol. Chem. 274: 17193-17201 [Abstract] [Full Text]
HO, I.-C., KIM, J.I., SZABO, S.J., GLIMCHER, L.H. (1999). Tissue-specific Regulation of Cytokine Gene Expression. Cold Spring Harb Symp Quant Biol 64: 573-584 [Abstract]
Barnes, P. J., Chung, K. F., Page, C. P. (1998). Inflammatory Mediators of Asthma: An Update. Pharmacol. Rev. 50: 515-596 [Abstract] [Full Text]
Schnare, M., Blum, H., Juttner, S., Rollinghoff, M., Gessner, A. (1998). Specific Antagonism of Type I IL-4 Receptor with a Mutated Form of Murine IL-4. J. Immunol. 161: 3484-3492 [Abstract] [Full Text]
Yu, C.-R., Kirken, R. A., Malabarba, M. G., Young, H. A., Ortaldo, J. R. (1998). Differential Regulation of the Janus Kinase-STAT Pathway and Biologic Function of IL-13 in Primary Human NK and T Cells: A Comparative Study with IL-4. J. Immunol. 161: 218-227 [Abstract] [Full Text]
Grunewald, S. M., Werthmann, A., Schnarr, B., Klein, C. E., Brocker, E. B., Mohrs, M., Brombacher, F., Sebald, W., Duschl, A. (1998). An Antagonistic IL-4 Mutant Prevents Type I Allergy in the Mouse: Inhibition of the IL-4/IL-13 Receptor System Completely Abrogates Humoral Immune Response to Allergen and Development of Allergic Symptoms In Vivo. J. Immunol. 160: 4004-4009 [Abstract] [Full Text]
Vernallis, A. B., Hudson, K. R., Heath, J. K. (1997). An Antagonist for the Leukemia Inhibitory Factor Receptor Inhibits Leukemia Inhibitory Factor, Cardiotrophin-1, Ciliary Neurotrophic Factor, and Oncostatin M. J. Biol. Chem. 272: 26947-26952 [Abstract] [Full Text]
Grunewald, S. M., Kunzmann, S., Schnarr, B., Ezernieks, J., Sebald, W., Duschl, A. (1997). A Murine Interleukin-4 Antagonistic Mutant Protein Completely Inhibits Interleukin-4-induced Cell Proliferation, Differentiation, and Signal Transduction. J. Biol. Chem. 272: 1480-1483 [Abstract] [Full Text]
Caput, D., Laurent, P., Kaghad, M., Lelias, J.-M., Lefort, S., Vita, N., Ferrara, P. (1996). Cloning and Characterization of a Specific Interleukin (IL)-13 Binding Protein Structurally Related to the IL-5 Receptor alpha Chain. J. Biol. Chem. 271: 16921-16926 [Abstract] [Full Text]
Zurawski, S. M., Chomarat, P., Djossou, O., Bidaud, C., McKenzie, A. N. J., Miossec, P., Banchereau, J., Zurawski, G. (1995). The Primary Binding Subunit of the Human Interleukin-4 Receptor Is Also a Component of the Interleukin-13 Receptor. J. Biol. Chem. 270: 13869-13878 [Abstract] [Full Text]
Obiri, N. I., Debinski, W., Leonard, W. J., Puri, R. K. (1995). Receptor for Interleukin 13. J. Biol. Chem. 270: 8797-8804 [Abstract] [Full Text]
Vita, N., Lefort, S., Laurent, P., Caput, D., Ferrara, P. (1995). Characterization and Comparison of the Interleukin 13 Receptor with the Interleukin 4 Receptor on Several Cell Types. J. Biol. Chem. 270: 3512-3517 [Abstract] [Full Text]
Smerz-Bertling, C., Duschl, A. (1995). Both Interleukin 4 and Interleukin 13 Induce Tyrosine Phosphorylation of the 140-kDa Subunit of the Interleukin 4 Receptor. J. Biol. Chem. 270: 966-970 [Abstract] [Full Text]