Recombinant IL-4 aggravates experimental autoimmune uveoretinitis in rats.
IL-4 is the critical regulatory cytokine that preferentially promotes a Th2 type of immune response. In certain models of organ-specific autoimmune diseases in which Th1 cells are implicated in the disease process, treatment with IL-4 has been shown to confer protection by deviating the immune response toward a Th2 type. In this study, we addressed the role of IL-4 in experimental autoimmune uveoretinitis, a prototypic Th1-dependent disease induced in susceptible animals following immunization with soluble retinal Ag. Interestingly, treatment of Lewis rats with IL-4 exacerbated experimental autoimmune uveoretinitis, and simultaneous treatment with neutralizing anti-IL-4 Abs attenuated this increase in the severity of the disease. Ex vivo analysis of cytokines produced in response to the immunizing Ag showed an enhancement in the levels of IFN-gamma, TNF-alpha, and nitric oxide following IL-4 treatment. In vitro, IL-4 augmented the production of IFN-gamma by Con A-stimulated splenocytes in a dose-dependent manner. At low concentrations of IL-4, IFN-gamma production was enhanced, while at higher concentrations this production was inhibited. The specificity of the induction of IFN-gamma by IL-4 was confirmed by neutralizing the activity of IL-4 with anti-IL-4. Taken together, the results herein reported demonstrate that IL-4 can induce the production of IFN-gamma and of inflammatory cytokines under certain conditions, and indicate that IL-4 can exert a dose-dependent differential effect on the induction of immune responses and on autoimmunity.
Ramanathan
S
S
INSERM Unit 430, Broussais Hospital, Paris, France.
de Kozak
Y
Y
Saoudi
A
A
Goureau
O
O
Van der Meide
P H
PH
Druet
P
P
Bellon
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000145:classification; D001324:Autoantigens / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000187:drug effects; D007132:Immunoglobulin Isotypes / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D015847:Interleukin-4 / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008627:Mercuric Chloride / Q000009:adverse effects; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects*; D012160:Retina / Q000276:immunology; D012173:Retinitis / Q000209:etiology* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D014605:Uveitis / Q000209:etiology* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001324:Autoantigens; D005136:Eye Proteins; D000949:Histocompatibility Antigens Class II; D007132:Immunoglobulin Isotypes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide; D008627:Mercuric Chloride; D007371:Interferon-gamma