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Introduction
type I cytokines

four-helix bundle

IL-6 / IL-23: differentiation into IL-17-producing cells

gp130 or IL-12R1

IL-12: promotes Th1 development

IL-27: antagonizes Th1, Th2 and Th17 responses

STAT pathways

IL-6

IL-23

IL-12

IL-27

Introduction
IL-12
IL-12p35 IL-12p40

IL-23
IL-23p19 IL-12/IL-23p40

IL-27
IL-27p28 EBI3 IL-35

Their secretion depends on regulated transcription of these subunits whereas these are always expressed

- IL-12p40 produced in excess = p40 homodimers function as IL-12 antagonists (Heinzel FP. 1997)

- unclear how the IL-27 subunits interact = secreted independently and associate with other proteins. IL-27 p28 and EBI3 are not produced by the same cells (Devergne O. 1996; Maaser C. 2004)

- IL-27p28, like IL-27, suppress IL-17 production in vitro (Stumhofer JS. 2006). How it happens?

Fig.1: EBI3 is not required for IL-27p28 secretion

IL-27p28 alone can inhibit IL-17 production?

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T gondii

IL-27p28 inhibitory effects are independent of EBI3 and its distinct from IL-27

Fig.2: IL-27p28 antagonizes gp-130mediated phosporilation.

*dose-dependent mechanism (5-50x) *similar results for IL-11 (use gp-130) *no effect for IL-12 (doesnt use gp-130)

IL-6

high biological activity even in very low concentrations

sIL-6Ra

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+p28

- p28 can interact with gp130 without EBI3 - greater hydrophobicity than IL-6

Fig.3: Phenotypic analysis of p28-tg mice

*p28-tg mice also have basal expression of IL-27p28
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p28-tg

WT

*no difference in the number of mature B cells *similar ratio CD4/CD8 but more in p28-Tg mice *more activated cells in p28Tg mice *similar number of Foxp3+ Treg (spleen)
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Fig.4: Tg overexpression of IL-27p28 antagonizes the activity of IL-6 and IL-27

*p28 Tg mice produce less IL17 and IL-10 in response to IL6 and IL-27 *lower STAT1/3 phosphorilation in p28 Tg mice

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Fig.5: Overexpression of IL-27p28 limits B cell responses

*many cytokines that use gp130 influence B cell development and Ab production *nave p28Tg mice have lower numbers of IgM/IgG-secreting B cells (SP, BM)

NP+Ficoll= thymus-independent Ag NP-CGG= thymus-dependent Ag *p28 does not affect IgM specific response to thymus-dependent or independent Ag

similar

similar

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*similar results after 56 days *similar B cell death in SP *p28Tg mice= no IgG in the serum (p28 prevents B cell development)

Low affinity
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High affinity

Fig.6: Tg overexpression of IL-27p28 blocks GC reactions

*p28Tg mice immunized with NP-CGG

*p28Tg mice do not form GC

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