Pro- and Anti-inflammatory Effects of IL-4: From Studies in Mice to Therapy of Autoimmune Diseases in Humans
Together the detailed analyses of the actions of IL-4 in various disease and immunization protocols indicated that one single cytokine may exert opposing effects on the development of immune responses. The biological effect of IL-4 depends on the primary target cell of this cytokine during an immune reaction, and factors such as the time of cytokine application and concentration during various phases of immune responses ultimately determine whether this cytokine has pro- or anti-inflammatory effects. Similar findings have been reported for other “paradoxical” cytokines, including IFN-γ, IL-10, and IL-12. Therefore the biological significance of cytokines and especially their use in clinical trials requires a critical review of the underlying animal experiments, including factors such as time, dose, and frequency of application.
KeywordsExperimental Allergic Encephalomyelitis Inflammatory Autoimmune Disease Immune Deviation Primary Target Cell Severe Experimental Allergic Encephalomyelitis
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- Biedermann T, Zimmermann S, Himmelrich H, Gumy A, Egeter O, Sakrauski AK, Seegmuller I, Voigt H, Launois P, Levine AD, Wagner H, Heeg K, Louis JA, Röcken M (2001b) IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat Immunol 2:1054–1060PubMedCrossRefGoogle Scholar
- Ebner S, Ratzinger G, Krosbacher B, Schmuth M, Weiss A, Reider D, Kroczek RA, Herold M, Heufler C, Fritsch P, Romani N (2001) Production of IL-12 by human monocyte-derived dendritic cells is optimal when the stimulus is given at the onset of maturation, and is further enhanced by IL-4. J Immunol 166:633–641PubMedGoogle Scholar
- Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, Van Eden W, Van Der Zee R, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlondorff D, Plewig G, Sander CA, Röcken M (2003) Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med 9:40–46PubMedCrossRefGoogle Scholar
- Himmelrich H, Launois P, Maillard I, Biedermann T, Tacchini-Cottier F, Locksley RM, Röcken M, Louis JA (2000) In BALB/c mice, IL-4 production during the initial phase of infection with leishmania major is necessary and sufficient to instruct Th2 cell development resulting in progressive disease. J Immunol 164:4819–4825PubMedGoogle Scholar
- Launois P, Gumy A, Himmelrich H, Locksley RM, Röcken M, Louis JA (2002) Rapid IL-4 production by Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells in resistant mice treated once with anti-IL-12 or-IFN-γ antibodies at the onset of infection with Leishmania major instructs Th2 cell development, resulting in nonhealing lesions. J Immunol 168:4628–4635PubMedGoogle Scholar
- Louis JA, Gumy A, Voigt H, Launois P, Röcken M (2003) The use of the murine model of infection with Leishmania major to reveal the antagonistic effects that IL-4 can exert on T helper cell development and demonstrate that these opposite effects depend upon the nature of the cells targeted for IL-4 signaling. Pathol Biol (Paris) 51:71–73PubMedCrossRefGoogle Scholar