The Second Signal in Antigen-Presenting Cells: Complementary JAK-1 Directs Pro- and Anti-Inflammatory Cytokine Production Induced by CD40L.

Abstract 1348

Poster Board I-371

Aberrant expression of CD40 ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. However, CD40 activation alone is unable to induce interleukin (IL)-12p70 secretion, whereas IL-6, IL-12p40, TNF-alpha and IL-10 are produced. We demonstrate that cytokine-induced Janus kinase (JAK)-1 is unique in mediating a complementary pro-inflammatory signal for the production of IL-12p70 whilst at the same time inhibiting IL-10 secretion in human APCs.

CD40- and JAK/STAT signals recruit complementary pathways: CD40 signals involve RelA and cRel for the induction of IL-12p70 and RelA for IL-10. In contrast, RelB inhibited IL-12p70 production. JAK1 complemented CD40-induced NF-kB signals by phosphorylating STAT-1 and inducing IRF-1 and IRF-8 expression resulting in IL-12p70 production. JAK-1-dependent inhibition of IL-10 transcription was mediated either by STAT-1 directly binding to the IL-10 promotor or by IRF-8 that in a complex with PU.1 (Spi-1) binds to inhibitory IFN-gamma-activated sequence (GAS)-sites of the IL-10 promotor. Our results demonstrate that specific inhibition of the “second signal” JAK1 will shift the balance of CD40-induced cytokine panels from IL-12p70 towards IL-10 in human APCs.