IFN-γ-Independent Autocrine Cytokine Regulatory Mechanism in Reprogramming of Macrophage Responses to Bacterial Lipopolysaccharide

Abstract

Macrophages are now well recognized to have a critical role in both innate and acquired immunity. The sentinel macrophage function is highly regulated and serves to allow for intrinsic plasticity of the innate immune responses to potential environmental signals. However, the mechanisms underlying the dynamic properties of the cellular arm of innate immunity are poorly understood. Therefore, we have conducted a series of in vitro studies to evaluate the contribution of immunoregulatory cytokines, such as IFN-γ, IL-10, and IL-12, in modulation of macrophage responses. We found that macrophages from IFN-γ knockout (IFN-γ−/−) mice exhibit only marginal LPS-induced TNF-α, IL-12, and NO responses, all of which can be fully restored in the presence of rIFN-γ. Pretreatment with substimulatory LPS concentrations led to reprogramming of IFN-γ−/− macrophage responses in a dose-dependent manner that manifested by an increased TNF-α and IL-12, but not NO, production upon the subsequent LPS challenge. These reprogramming effects were substantially attenuated and profoundly enhanced in macrophages from IL-12−/− and IL-10−/− mice, respectively, as compared with those modulated in macrophages from the congenic wild-type mice. LPS-dependent reprogramming was also fully reproduced in macrophages isolated from SCID mice after immunodepletion of NK cells. Our data strongly imply that cytokine (TNF-α and IL-12), but not NO, responses in macrophages may, at least in part, be governed by an autocrine IFN-γ-independent regulatory mechanism reciprocally controlled by IL-10 and IL-12. This mechanism may serve as an alternative/coherent pathway to the canonical IFN-γ-dependent induction of antimicrobial and tumoricidal activity in macrophages.

Controlled Modulation of Inflammatory, Stress and Apoptotic Responses in Macrophages

“…(reviewed in [61]). Recently published experiments have led to the development of the concept of LPS-dependent reprogramming or priming of macrophages for either pro-inflammatory or anti-inflammatory responses [1][2][3], which has also been described by others as classical and alternative activation of macrophages [62,63]. In our experiments we used thioglycollate-elicited peritoneal macrophages harvested from C3HeB/FeJ mice 4 days after injection of 1.5 ml of sterile 4% broth.…”

“…Such differential modulation of macrophage responses in vitro was termed reprogramming. Furthermore, accumulated experimental evidence strongly suggests that LPS-dependent reprogramming differentially modulates IL-1β, IL-6, IL-10, and IL-12 responses in macrophages by IFN-γ-independent autocrine cytokine regulatory mechanisms [2,3] and that induction of these distinct phenotypic responses is controlled at the transcriptional level by selective activation and nuclear translocation of NF-κB and Stat1 transcriptional factors (Shnyra et al, unpublished data). Consequently, the phenomenon of macrophage reprogramming has allowed us to propose a general concept of macrophage-dependent regulatory mechanisms of innate immunity in providing the regulatory signals for the development of acquired immune responses to microbial pathogens [2].…”

TNFα- and NF-κB-dependent induction of the chemokine CCL1 in human macrophages exposed to the atherogenic lipoprotein(a)

“…Since macrophages constitute a major producing source of cytokines which can act as autocrine factors affecting macrophagic functions (Vila-del Sol et al 2007), including secretion of cytokines/ chemokines (Brewington et al 2001), we next investigated whether the factor, whose de novo synthesis is required for Lp(a)-related induction of CCL1 (Fig. 2C), may be a cytokine.…”

The Role of Acquired Immunity and Periodontal Disease Progression

“…Further investigation is required to determine whether signaling via specific TLRs would preferentially induce Th1 development (Jotwani et al, 2001;Pulendran et al, 2001;Schnare et al, 2001). Further, this IL-12-mediated Th1 development is often achieved via an IFN-␥-dependent and, to a lesser degree, by IFN-␥-independent mechanisms (Brewington et al, 2001). Therefore, DCs can be tuned to express certain "biasing" cytokines (i.e., IL-12, IL-10) to promote or to minimize the development of cytokine-mediated immunopathology (Reis e Sousa et al, 1999;Jotwani et al, 2001).…”