J Leukoc Biol. 2014 Jan 13.

Oral delivery of oligomeric procyanidins in Apple Poly(R) enhances type I IFN responses in vivo.

Snyder DT, Robison A, Kemoli S, Kimmel E, Holderness J, Jutila MA, Hedges JF.

Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, USA.



Type I IFN signaling is a central pathway that provides critical innate protection from viral and bacterial infection and can have regulatory outcomes in inflammatory settings. We determined previously that OPCs contained in the dietary supplement APP enhanced responses to type I IFN in vitro. Here, we confirm that OPCs from two different sources significantly increased pSTAT1, whereas a monomeric form of procyanidin did not. We hypothesized that similar responses could be induced in vivo following ingestion of APP. Ingestion of APP before injection of polyI:C enhanced in vivo responses to type I IFNs in mice. When human subjects ingested APP, enhanced responses to type I IFN and enhanced pSTAT1 ex vivo were detected, whereas ingestion of RES, a monomeric polyphenol, induced minimal such changes. Polyphenols are best known for induction of anti-inflammatory and antioxidant responses; however, our findings suggest a unique, nonantioxidant aspect of OPCs that is broadly applicable to many disease settings. The capacity of oral OPCs to enhance type I IFN signaling in vivo can augment innate protection and may, in part, contribute to the noted anti-inflammatory outcome of ingestion of OPCs from many sources.

KEYWORDS: autoimmune; complementary therapy; innate antiviral

PMID: 24421266



Polyphenols are a class of large chemical compounds found in a wide range of foods and dietary supplements, such as pomegranates, grapes, and tea, and are thought to have a variety of health benefits (1-3). Americans ingest an average of 1g of polyphenols per day (4), which underscores their ubiquity and safety. Applepoly® (APP) is an extract from unripe apple peel that contains high concentrations of specific polyphenols, oligomeric procyanidins (OPCs) (3,5). Continuous intake of polyphenol-containing supplements, including APP, have been associated with anti-inflammatory effects consistent with their well-known capacity for antioxidant activity (6). We have demonstrated that OPCs can have multiple novel effects on immunity (5,7,8), including enhanced responses to type I interferon (IFN) in vitro (9) and, importantly, in vivo following ingestion (10). The latter effect was surprisingly long lasting; a minimal dose of APP had effects detectible after several weeks. It is thus feasible that APP ingestion could contribute to diminished inflammation in human patients through a mechanism dependent on type I IFN signaling.

Type I IFN is best known for its protective effects in antiviral immunity, but clearly has anti-inflammatory effects in some settings. For example, interferon β (IFN- β) has long been used as a therapy for Multiple Sclerosis (MS) patients (11). MS is one of many inflammatory diseases with increasing incidence in the developed world and there are few therapeutic options for MS treatment. Evidence suggests that type I IFN induces the anti-inflammatory cytokines IL-27 (12) and IL-10 (13) which results in amelioration of inflammatory conditions in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. We detected enhanced induction of these cytokines in blood cells from human subjects that ingested APP (10). There are numerous complications with IFN therapy in human MS patients. Clearly, a combination oral treatment that augments anti-inflammatory effects of type I IFN, such as APP, may increase efficacy, or decrease the dose, of this therapy. Furthermore, enhancing responses to endogenously-expressed type I IFNs could obviate the need for any additional therapy. There are virtually no cures for debilitating autoimmune conditions, and inventive therapeutic approaches are clearly warranted. Enhancing type I IFN signaling in MS patients could provide a significant benefit.

Recent evidence suggests that several autoimmune inflammatory disorders are related to dysregulation in intestinal microbiota (14). Considering the rapid increase of such disorders, environmental factors such as diet, antibiotic use, environment, and even delivery by cesarean section likely combine with host genetics to affect the composition of the microbiota (14). Thus, living in modern industrialized societies has resulted in microbiotic populations that are substantially different from those in undeveloped societies, where autoimmune and inflammatory diseases are much less common. The specific composition of intestinal microbiota has been recognized for its substantial impact on immunity. Increases in the phylum Bacteroidetes relative to Firmicutes are associated with anti-inflammatory outcomes (15). Of note, ingestion of polyphenols has been associated with an increase in the more healthful phylum Bacteroidetes (4). Microbiota has a critical role in autoimmune conditions, such as EAE, and may hold therapeutic potential (15). Little is currently known about a connection between IFN signaling and the microbiome, but a study in piglets suggested that the presence of a healthy microbiota induced signaling in both the IFNAR and IFN-g pathways when compared to germfree piglets (16). Whether specific populations in the microbiome affect these pathways preferentially is not currently known. The possibility of significantly altering immunity through microbiota to potentially reverse current inflammatory states induced by environment, using a safe and readily available dietary supplement, represents an exciting prospect and a novel approach for debilitating autoimmune conditions. Thus, effects of APP ingestion on intestinal microbiota should also be investigated to further elucidate mechanisms of in vivo effects. Ingestion of APP or other rich sources of similar OPCs may represent a novel therapeutic approach, for use alone or as a combination therapy, in any setting in which enhanced type I IFN signaling would benefit.

Importance of this study: We have noted that APP can have substantial impact on specific immune responses of cells in culture. This study demonstrated that ingestion of a minimal dose of APP had a long lasting effect of enhancing type I IFN signaling. This study is important because this effect was measured not only in mice, but in outbred human subjects with diverse diets and life experiences. Because the supplement is safe to ingest, we believe it will be helpful whenever enhanced responses to type I IFN expression would be beneficial. Most notably this would be during cold and flu season or when a viral infection threatens. Our evidence suggests that it may also benefit in autoimmune inflammatory states in which type I IFN is already known to benefit.



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This project was primarily funded through NIH COBRE (P20 RR020185), with partial funding through NIH-NCCAM (AT0004986-01), M.J. Murdock Charitable Trust and The Montana State University Agricultural Experimental Station.


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