Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells

HEIJINK, IRENE H.
VELLENGA, EDO
BORGER, PETER
POSTMA, DIRKJE S.
DE MONCHY, JAN G. R.
KAUFFMAN, HENK F.

^*Department of Allergology, University Hospital Groningen, Groningen, the Netherlands
†Department of Hematology, University Hospital Groningen, Groningen, the Netherlands
‡Department of Pulmonology, University Hospital Groningen, Groningen, the Netherlands

Correspondence: Dr H. F. Kauffman, Department of Allergology, University Hospital Groningen, Hanzeplein 1, NL-9713 GZ, Groningen, the Netherlands. E-mail: [email protected]

Abbreviations: AP-1, activator protein; BAL, bronchoalveolar lavage; CsA, cyclosporin A; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-related kinase; IL, interleukin; IFN, interferon; MAP, mitogen activated protein; JNK, c-Jun N-terminal kinase; MEK, MAPK/ERK kinase; NF-AT, nuclear factor of activated T cells; PI3-kinase, phosphatidylinositol 3-kinase; PKC, protein kinase C; rh, recombinant human; RT–PCR, reverse transcriptase–polymerase chain reaction; SOCS, suppressor of cytokine signalling; STAT, signal transducer and activator of transcription; TBE, TRIS boric acid EDTA; Th, T helper.

Received 20 February 2002; revised 21 June 2002; accepted 4 July 2002.

Immunology 107(3):p 316-324, November 2002.

SUMMARY

T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in the development of allergic immune responses. After allergen provocation, the expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is a multifunctional cytokine that is able to direct Th2 immune responses and is secreted by multiple tissue cell types. This study shows that IL-6 induces up-regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly isolated, α-CD3/α-CD28-stimulated T cells. After longer preincubation periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a small but significant inhibitory effect is found on the production of the Th1 cytokine interferon-γ. Additional experiments indicate that the long-term priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38 mitogen-activated protein kinase-dependent induction of activator protein-1 DNA-binding activity is involved, independent of signal transducer and activator of transcription 3 phosphorylation. In summary, these data demonstrate that the short-term and long-term priming effects of IL-6 on Th2 cytokine production are regulated by different mechanisms.