DIRECT CONTACT WITH STIMULATED T CELLS INDUCES THE EXPRESSION OF IL-1β AND IL-1 RECEPTOR ANTAGONIST IN HUMAN MONOCYTES. INVOLVEMENT OF SERINE/THREONINE PHOSPHATASES IN DIFFERENTIAL REGULATION

193

216

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-α, IL-6, and IFN-γ) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-α and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of “tolerance.” ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

McInnes

Leung

Harnett

et al. 2003

193

216

“…MAPK such as Raf-1 and ERK1/ERK2 have been involved in sIL-1Ra induction by LPS and leptin (29,30). In contrast, serine/threonine phosphatases are involved in the induction of sIL-1Ra in monocytic cells activated by cellular contact with stimulated T cells (31), and STAT6 mediates the induction of sIL-1Ra by IL-4 (32). Furthermore, an LPS-inducible PI3K-dependent signaling pathway contributes to the elevated translation of sIL-1Ra in septic/LPSadapted leukocytes, a pathway that does not affect the production of IL-1␤ (33).…”

Section: Nterleukin-1 Receptor Antagonist (Il-1ra)mentioning

confidence: 99%

The Production of IL-1 Receptor Antagonist in IFN-β-Stimulated Human Monocytes Depends on the Activation of Phosphatidylinositol 3-Kinase but Not of STAT1

Molnarfi

Hyka‐Nouspikel

Gruaz

et al. 2005

Self Cite

IFN-β induces the production of secreted IL-1R antagonist (sIL-1Ra) without triggering synthesis of the agonist IL-1β in human monocytes. This might account for its anti-inflammatory properties. Canonically, IFN-β signals through activation of JAK/STAT pathway, although PI3K and MAPK have also been involved. In this study, the role of PI3K, MEK1, and STAT1 in IFN-β-induced sIL-1Ra production is investigated in freshly isolated human blood monocytes. PI3K, but not MEK1 activation is essential for sIL-1Ra production in monocytes treated with IFN-β, as demonstrated by using the respective inhibitors of PI3K and MEK1, Ly294002 and PD98059. The use of cycloheximide and actinomycin D shows that sIL-1Ra was an immediate early gene induced by IFN-β and that PI3K was controlling sIL-1Ra gene transcription. Although both inhibitors of PI3K and MEK1 diminished the Ser727 phosphorylation of STAT1 induced by IFN-β, only Ly294002 inhibited sIL-1Ra production. Furthermore, the inhibition of STAT1-Ser727 phosphorylation by Ly294002 did not affect STAT1 translocation, suggesting that STAT1 was not involved in sIL-1Ra gene induction. This was confirmed in monocytes that were transfected with small interfering RNA specifically targeting STAT1. Indeed, monocytes in which effective STAT1 gene knockdown was achieved were fully responsive to IFN-β in terms of sIL-1Ra production. Taken together, the present data demonstrate that the induction of sIL-1Ra transcription and production by IFN-β in human monocytes involved PI3K, but not STAT1 activation.

“…Considering that the production of IL-1␤ and sIL-1Ra is tightly controlled in time, the signaling pathways leading to their production have to be distinct while triggered by the same stimulus. We previously demonstrated that serine-threonine phosphatases play a part in the differential regulation of IL-1␤ and sIL-1Ra production by the monocytic cell line THP-1 when activated by contact with stimulated T cells (26). In contrast, IFN-␤, which induces the production of sIL-1Ra without inducing that of IL-1␤ in isolated human blood monocytes (27), differentially modulates the production of cytokines induced by either cellular contact or LPS (25).…”

mentioning

confidence: 99%

Opposite Regulation of IL-1β and Secreted IL-1 Receptor Antagonist Production by Phosphatidylinositide-3 Kinases in Human Monocytes Activated by Lipopolysaccharides or Contact with T Cells

Molnarfi

Gruaz

Dayer

et al. 2007

Self Cite

The unbalanced production of IL-1β and its natural, specific inhibitor, the secreted IL-1R antagonist (sIL-1Ra), plays an important role in chronic/sterile inflammation. Relevant to this condition is direct cellular contact with stimulated T cells which is a potent inducer of cytokine production in human monocytes/macrophages. We previously demonstrated that activation of PI3Ks is a prerequisite of the transcription of the sIL-1Ra gene in human monocytes activated by IFN-β. In this study, we addressed the question of PI3K involvement in the production of IL-1β and sIL-1Ra in monocytes activated by cellular contact with stimulated T cells (mimicked by CHAPS-solubilized membranes of stimulated T cells (CEsHUT)), and a crude preparation of LPS, to compare stimuli relevant to chronic/sterile and acute/infectious inflammation, respectively. In monocytes activated by either CEsHUT or LPS, the inhibition of PI3Ks abrogated sIL-1Ra transcript expression and sIL-1Ra production, demonstrating that PI3Ks control the induction of sIL-1Ra gene transcription. In contrast, PI3K inhibition increased the production of IL-1β protein in both CEsHUT- and LPS-activated monocytes, the enhancement being drastically higher in the former. This was not due to changes in IL-1β mRNA steady-state levels or transcript stability, but to the involvement of PI3Ks in the repression of IL-1β secretion. The downstream PI3K effector, Akt, was implicated in this process. The present results demonstrate that PI3Ks are involved in the inhibition of IL-1β secretion and in the induction of sIL-1Ra production in human blood monocytes by controlling different mechanisms in conditions mimicking chronic/sterile (CEsHUT) and acute/infectious (LPS) inflammation.