Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection

IFN-κ is a recently identified type I IFN that exhibits both structural and functional homology with the other type I IFN subclasses. In this study, we have investigated the effect of IFN-κ on cells of the innate immune system by comparing cytokine release following treatment of human cells with either IFN-κ or two recombinant IFN subtypes, IFN-β and IFN-α2a. Although IFN-α2a failed to stimulate monocyte cytokine secretion, IFN-κ, like IFN-β, induced the release of several cytokines from both monocytes and dendritic cells, without the requirement of a costimulatory signal. IFN-κ was particularly effective in inhibiting inducible IL-12 release from monocytes. Unlike IFN-β, IFN-κ did not induce release of IFN-γ by PBL. Expression of the IFN-κ mRNA was observed in resting dendritic cells and monocytes, and it was up-regulated by IFN-γ stimulation in monocytes, while IFN-β mRNA was minimally detectable under the same conditions. Monocyte and dendritic cell expression of IFN-κ was also confirmed in vivo in chronic lesions of psoriasis vulgaris and atopic dermatitis. Finally, biosensor-based binding kinetic analysis revealed that IFN-κ, like IFN-β, binds strongly to heparin (Kd: 2.1 nM), suggesting that the cytokine can be retained close to the local site of production. The pattern of cytokines induced by IFN-κ in monocytes, coupled with the unique induction of IFN-κ mRNA by IFN-γ, indicates a potential role for IFN-κ in the regulation of immune cell functions.

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Regulatory Effect of IFN-κ, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System

Nardelli

Zaritskaya

Semenuk

et al. 2002

“…Studies show that during murine cytomegalovirus and lymphocytic choriomeningitis virus infection, endogenous IFN-␣␤ inhibit IL-12 and IFN-␥ production (54). The low levels of IFN-␣␤ in C. pneumoniae-infected mice are probably not sufficient for inhibition of IL-12, which therefore governs IFN-␥ production in vivo (33).…”

Section: Discussionmentioning

confidence: 99%

STAT1 Regulates IFN-αβ- and IFN-γ-Dependent Control of Infection withChlamydia pneumoniaeby Nonhemopoietic Cells

Rothfuchs

Trumstedt

Mattei

et al. 2006

STAT1 mediates signaling in response to IFN-α, -β, and -γ, cytokines required for protective immunity against several viral, bacterial, and eukaryotic pathogens. The protective role of STAT1 in the control of intranasal infection with the obligate intracellular bacterium Chlamydia pneumoniae was analyzed. IFN-γ−/− or IFN-γ receptor (R)−/− mice were highly susceptible to infection with C. pneumoniae. We found that STAT1−/− mice were even more susceptible to C. pneumoniae than IFN-γ−/− or IFN-γR−/− mice. Phosphorylation of STAT1 was detected in the lungs of C. pneumoniae-infected wild-type, IFN-γR−/−, and IFN-αβR−/− mice, but not in mice lacking both IFN-αβR and IFN-γR. In line with this, IFN-αβR−/−/IFN-γR−/− mice showed increased susceptibility to infection compared with IFN-γR−/− mice. However, C. pneumoniae-infected IFN-αβR−/− or IFN regulatory factor 3−/− mice showed no increased susceptibility and similar IFN-γ expression compared with wild-type mice. CD4+ or CD8+ cells released IFN-γ in vivo and conferred protection against C. pneumoniae in a STAT1-independent manner. In contrast, STAT1 mediated a nonredundant protective role of nonhemopoietic cells but not of hemopoietic cells. Nonhemopoietic cells accounted for the expression of STAT1-mediated indoleamine 2, 3-dioxygenase and the p47 GTPase LRG-47, but not inducible NO synthase mRNA. In summary, we demonstrate that STAT1 mediates a cooperative effect of IFN-αβ and IFN-γ on nonhemopoietic cells, resulting in protection against C. pneumoniae.

“…Our group has previously shown that IFN-␣␤ function to inhibit endogenous IL-12 expression during LCMV infection (11). In addition, 2 days after viral infections, IFN-␣␤ induce a refractory state in which NK cell IFN-␥ responses to IL-12 and anti-CD3-elicited IFN-␥ production from splenocytes are inhibited (69).…”

Section: Discussionmentioning

confidence: 99%

A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections

Pien

Nguyen

Malmgaard

et al. 2002

The kinetics of CD8 T cell IFN-γ responses as they occur in situ are defined here during lymphocytic choriomeningitis virus (LCMV) infections, and a unique mechanism for the innate cytokines IFN-αβ and IL-18 in promoting these responses is defined. Infections of mice with Armstrong or WE strains of LCMV induced an unexpectedly early day 4 IFN-γ response detectable in serum samples and spleen and liver homogenates. Production of IFN-γ was MHC class I/CD8 dependent, but did not require IL-12, NK cells, TCR-γδ T cells, MHC class II, or CD4 T cells. Peak response required specific Ag recognition, as administration of antagonist peptide partially impaired day 4 IFN-γ induction, and viral peptide stimulation enhanced CD8 T cell IFN-γ expression in culture. The IFN-γ response was associated with IL-18 and IFN-αβ expression. Furthermore, both factors augmented peptide-driven IFN-γ production in culture, and mice lacking IL-18 or IFN-αβ functions had reduced day 4 IFN-γ. Collectively, these results demonstrate that during viral infections, there is a dramatic in vivo CD8 T cell response preceding maximal expansion of these cells, and that the mechanism supporting this response is dependent on endogenous innate cytokines. Because stimulation by microbial products is linked to innate cytokine expression, the studies also suggest a pathway for precisely limiting T cell functions to times of need.