PI3K-mediated negative feedback regulation of IL-12 production in DCs

Abstract

Although interleukin 12 (IL-12) production by dendritic cells (DCs) confers protection against harmful invasions by regulating both innate and adaptive immunity, its dysregulation may have detrimental effects on the host. We show here that phosphoinositide 3-kinase (PI3K) negatively regulates IL-12 synthesis by DCs. We found that numerous stimuli that induced IL-12 production concomitantly elicited PI3K activation in DCs, but both PI3K(-/-) and PI3K inhibitor#150;treated DCs showed increased IL-12 production. Accordingly, an enhanced T helper type 1 (T(H)1) response was observed upon Leishmania major infection in PI3K(-/-) mice. Our findings indicate that a negative feedback mechanism exists that regulates IL-12 production during DC activation and may help prevent the excessive T(H)1 polarization that causes undesirable immune responses.

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

“…Indeed, class I A PI3K-deficient mice were found to develop increased T helper type 1 (Th1) response upon Leishmania major infection [16] and pharmacological inhibition of PI3K activity exacerbates microbial sepsis [17]. The findings reported here indicate that the net result of PI3K inhibition in the course of infections could be cumulatively influenced by the up-regulation of IFN-b synthesis if TLR3 or TLR4 (or both) are engaged by pathogen-associated molecular patterns.…”

“…Recent reports provided evidence that PI3K are part of an intracellular control mechanism regulating the initial phases of innate immune responses to diverse microbial pathogens [37]. In DC and macrophages, activation of PI3K-Akt axis was found to limit LPS-induced production of IL-12 and TNF-a and expression of nitric oxide synthase (NOS) that occurs mainly through the MyD88-dependent pathway [16,[18][19][20]. We have demonstrated that inhibition of PI3K activity enhances type I IFN-b gene expression in response to LPS, indicating an action on the MyD88-independent TLR4 signaling pathway.…”

“…Recent studies provided evidence that PI3K regulates innate responses to microbial pathogens [16,17] and limits the production of inflammatory mediators in response to bacterial LPS [18][19][20][21][22]. PI3K was shown to regulate MyD88-dependent events [23][24][25][26] but its role in the TRIF-dependent signaling cascade has not been demonstrated so far.…”

CpG- and LPS-activated MAPK signaling in in vitro cultured salmon (Salmo salar) mononuclear phagocytes

“…However, another explanation is the potential autocrine action of M-CSF, or analogous growth factors, since in primary murine macrophages the p38 activation by CpGs, but not LPS, was suppressed by pretreatment with M-CSF which at the same time upregulated ERK phosphorylation [36]. In addition, it has been shown that the PI3K signalling suppresses TLR-induced p38 phosphorylation in innate immune cells including DCs [37] and macrophages [38]. Enhanced activity of PI3K in macrophages results in increased DUSP1 (a p38 specific phosphatase) expression, IL-10 production and, as a result, diminished p38 activation and lowered production of proinflammatory cytokines in response to pathogens [39].…”

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

“…Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.…”