Interesting Study - FOXO proteins and immune function
In my usual, nerdy, fun-filled weekend morning reading of recent pubmed articles on inflammation, I ran across a study on FOXO proteins and their importance in healthy immune functioning. I'd never heard anything about these proteins before, so I did some googling and came across some interesting studies that I thought I would post.
First, FOXO proteins are a subgroup of the Forkhead (FOX) family of transcription factors, and as the following article points out:
"FOXO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle progression, and oxidativestress resistance (Figure 1). For example, FOXO factors can initiate apoptosis by activating transcription of FasL, the ligand for the Fas-dependent celldeath pathway, and by activating the pro-apoptotic Bcl-2 family member Bim. Alternatively, FOXO factors can promote cellcycle arrest; for example, FOXO factors upregulate the cell-cycle inhibitor p27kip1 to induce G1 arrest or GADD45 to induce G2 arrest. FOXO factors are also involved in stress resistance via upregulation of catalase and MnSOD, two enzymes involved in the detoxification of reactive oxygen species. Additionally, FOXO factors facilitate the repair of damaged DNA by upregulating genes, such as GADD45 and DDB1. Other FOXO target genes have been shown to play a role in glucose metabolism, cellular differentiation, muscle atrophy, and even energy homeostasis."
Interestingly, as the following easy to read article on a recent study points out, it is believed FOXO transcription factor is influenced by diet, and importantly, FOXO is believed to be an important regulator of antimicrobial peptide (AMP) induction:
"in the case of a low insulin level the FOXO transcription factor is activated. A transcription factor can switch genes on and off. FOXO switches genes for immune defence proteins on when energy is needed. These antimicrobial peptides (AMP) -- not to be confused with antibodies -- are subsequently jettisoned by the body's cells. They destroy possible pathogens by dissolving their cell walls."
The following article mentions the above article and points out that antimicrobial peptides are activated in response to nuclear FOXO activity and reductions of nuclear levels of FOXO may lead to increased infection:
"It has recently been shown in Drosophila that the induction of antimicrobial peptides (AMPs) can be achieved independently of tolllike receptor (TLR) pathways by FoxO-dependent gene regulation. AMP genes are activated in response to nuclear FoxO activity . Increased growth factor signaling of puberty and insulinotropic Western diet may reduce nuclear levels of FoxO1 and AMP activity thus promoting P. acnes growth and biofilm formation."
The article also discusses phosphoinositol-3 kinase(PI3K)/Akt activation and its function in decreasing nuclear FOXO levels:
"The activated kinase Akt (protein kinase B) translocates into the nucleus where Akt phosphorylates the nuclear FoxO1 protein. Phosphorylated FoxO1 is exported from the nucleus into the cytoplasm thereby derepressing target genes"
And the article lists various known growth factors and stimuli for phosphoinositol-3 kinase(PI3K)/Akt activation, including, Insulin, IGF-1 and even Nicotin (see Figure 1).
The article goes on to discuss high glycemic diets and its effects on IGF-1 and insulin levels:
"Nutrients rich in carbohydrates with a high glycemic index (GI) induce hyperglycemia, reactive hyperinsulinemia, and increased IGF- 1 serum levels. In contrast, a diet with a low glycemic load decreased serum IGF-1 levels..."
And interestingly, the article discusses dairy consumption and its apparently rather dramatic effects on serum IGF-1 levels:
"Milk consumption induces high serum levels of IGF-1 [11-15]. Milk consumption has been associated with linear growth and the manifestation of acne [16-18]. It is the biologic principle of milk to promote growth by increased insulin/IGF-1 signaling and induction of insulin resistance [11,12,15,19-23]. The relation between milk induced insulin/IGF-1 signaling and the pathogenesis of acne and chronic diseases of Western civilization has recently been presented [7,10,24-27]. The insulinotropic effect of milk resides within the hydrophilic whey protein fraction . Both insulin and IGF-1 reduce nulear levels of FoxO1 [2,3]."
While I'm certainly no expert, I found this interesting and potentially another piece of the puzzle. All of this all got me thinking, could my dairy consumption be interfering with proper immune function and my return to good health? It should be easy enough to give up dairy for a while, so I thought I'd give this a try, changing nothing else in my diet other than complete elimination of dairy. For me, this really only means no milk in my morning coffee, and no cheese at lunch or dinner anyway. Not a big deal at all...
Certainly I need to give this a longer go, but after only a couple of days, I've started noticing a lot of now unusual aches and pains, some fairly decent amount of fatigue and even some dizziness upon standing and odd muscle twitching that I have not seen in years - all tell tale signs for me of a large increase in die-off of something. Perhaps there is something in this?
Anyway, more later, but I thought I'd pass this along in case it might help...
Hang in there...