Recombinant soluble interleukin-4 (IL-4) receptor acts as an antagonist of IL-4 in murine cutaneous Leishmaniasis.
This study was performed to evaluate the soluble interleukin-4 receptor (sIL-4R) as a potential antagonist of interleukin-4 (IL-4) in an infectious disease. It is shown that antigen-triggered proliferation and cytokine secretion of Leishmania major-specific, cloned Th2 cells in vitro can be inhibited dose dependently by recombinant murine, but not control human, sIL-4R. In vivo, we found that endogenous synthesis of IL-4 mRNA is upregulated during the first week of infection, while an increase of IL-4R mRNA occurred later after infection of BALB/c mice with L. major. To interfere successfully with the IL-4 ligand-receptor interaction, we therefore chose to treat infected BALB/c mice with recombinant sIL-4R during the onset (e.g., days 0 to 7) of the immune response. Treatment with murine, but not with human, sIL-4R during the first week of infection rendered BALB/c mice clinically resistant to L. major, led to a 7- to 12-fold reduction of the parasite load in spleen and lymph nodes at 7 weeks of infection, shifted the pattern of cytokines towards a Th1 type, and provided durable resistance against reinfection. Thus, it could be demonstrated that the balance among sIL-4R, membrane-bound IL-4R, and their ligand IL-4 can be modulated in vivo, thereby modifying the antiparasitic immune response. These results suggest a therapeutic value of sIL-4R in diseases in which neutralization of IL-4 is desirable.
Gessner
A
A
Institut für Klinische Mikrobiologie und Immunologie, Universität Erlangen-Nürnberg, Federal Republic of Germany.
Schröppel
K
K
Will
A
A
Enssle
K H
KH
Lauffer
L
L
Röllinghoff
M
M
D000818:Animals; D001483:Base Sequence; D005260:Female; D015847:Interleukin-4 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4