IL-10 and viral IL-10 prevent IL-4-induced IgE synthesis by inhibiting the accessory cell function of monocytes.
In the present study it is demonstrated that IL-10 and viral (v)-IL-10 inhibit IL-4-induced IgG4 and IgE synthesis in cultures of PBMC from healthy nonatopic donors. The inhibition occurred at the mRNA level. IL-10 strongly reduced IL-4-induced expression of both germline and productive epsilon transcripts in PBMC. The inhibitory effects were completely neutralized, or IgG4 and IgE synthesis was even enhanced, by anti-IL-10 mAb, demonstrating the specificity of the reaction. IL-4-induced IgG4 and IgE synthesis by PBMC was monocyte dependent. IL-4 failed to induce IgG4 or IgE synthesis by monocyte-depleted PBMC, but the production of these isotypes was completely restored by reconstitution with autologous monocytes. However, monocytes preincubated with IL-10 for 24 h failed to provide the accessory signals required for IL-4-induced IgG4 and IgE synthesis, indicating that the inhibitory effects of IL-10 are indirectly mediated via monocytes. This notion was further supported by the finding that IL-10 and v-IL-10 failed to inhibit IL-4-induced IgE synthesis in the absence of monocytes, i.e., when highly purified B cells were cultured in the presence of anti-CD40 mAb or cloned activated CD4+ T cells. Moreover, IL-10 failed to inhibit IL-4-induced germline epsilon mRNA synthesis in highly purified B cells. The inhibitory effects of IL-10 could not be restored by exogenous TNF-alpha or IL-6, indicating that the inhibitory effects were not mediated through inhibition of production of these cytokines. This is compatible with the observation that monocytes preincubated with IL-10 did not inhibit IgG4 or IgE synthesis in a monocyte- and T cell-independent culture system, in which purified B cells were cultured in the presence of anti-CD40 mAb and IL-4. Collectively, these data indicate that IL-10 mediates a potent, monocyte-dependent, inhibitory effect on IL-4-induced IgG4 and IgE production by human PBMC.
DNAX Research Institute of Molecular and Cellular Biology, Human Immunology Department, Palo Alto, CA 94304-1104.
J
J
Punnonen
R
R
de Waal Malefyt
P
P
van Vlasselaer
J F
JF
Gauchat
J E
JE
de Vries
D000938:Antigen-Presenting Cells / Q000276:immunology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000494:pharmacology*
C066460:BCRF1 protein, Human herpesvirus 4; D007074:Immunoglobulin G; D007139:Immunoglobulin epsilon-Chains; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007073:Immunoglobulin E