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Published in final edited form as: J Neurol Sci. 2019 Nov 27;409:116602. doi: 10.1016/j.jns.2019.116602

Ingested ACTH blocks Th17 production by inhibiting GALT IL-6

Landon J Dittel a, Bonnie N Dittel b, Staley A Brod c,*
PMCID: PMC10394755  NIHMSID: NIHMS1921081  PMID: 31812846

Abstract

Background:

EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown.

OBJECTIVE:

IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE.

Design/methods:

B6 mice were immunized with MOG peptide 35–55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1–39 during ongoing disease.

Results:

Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 +FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS.

Conclusions:

Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.

Keywords: Oral proteins, ACTH, IL-17, IL-6, EAE, Lamina propria

1. Introduction

EAE is a T cell mediated inflammatory autoimmune process of the CNS that resembles in some aspects the human demyelinating disease multiple sclerosis (MS) [1] and provides a useful animal model for the evaluation of potential therapies for autoimmune diseases [2–4]. Inoculation of B6 mice with MOG peptides can activate pathogenic neuroantigen-specific Th17 T helper cells in vivo and produce inflammation in murine EAE [5,6].

In the murine system, class II restricted helper T cells have been separated into 3 major non-overlapping subsets according to their interleukin gene secretion [7–11]. One subset (Th1) secretes IL-2 and IFN-γ regulating delayed type hypersensitivity (DTH) responses and inflammation in EAE. Another subset (Th2) produces anti-inflammatory cytokines IL-4, IL-10 and IL-13 that inhibit EAE. A 3rd subset (Th17) produces IL-17 and IL-21 that can generate autoimmunity [12].

Th17 cells are constitutively present throughout the gut associated lymphoid tissue (GALT), in particular the intestinal lamina propria (LP) and Peyer’s patches (PP) [13]. Pathogenic Th17 differentiation is initiated by IL-1 [14], IL-6 [15] and TGF-β [16], and reinforced by IL-23 [17] during the development of IL-17 producing cells originating in the GALT [18]. IL-6 inhibits the generation of Treg cells induced by TGF-β. Therefore, the presence or absence of IL-6 is critical for the balance of Th17 vs Treg cells in GALT [19]. GALT LP CD11b + DC subset secrete higher levels of IL-6 compared with other DC subsets [20–22]. CD4+ Th2 cells can also produce IL-6 [23].

Ingested immunoactive proteins can decrease IFN-γ Th1-like encephalitogenic activity (ingested IFN-α) [24–27], Th1-like encephalitogenic cytokines IL-2 (oral alpha-MSH) [25] and increase Th2-like counter-regulatory cytokines (oral SIRS peptide) [24]. Oral ACTH also decreases clinical scores and the secretion of IL-17 (Teff) and Th1-like encephalitogenic cytokine IFN-γ [28]. Previous investigators have shown that IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis [29]. However, it is not known if the mechanism of action of oral ACTH in the GALT occurs through the inhibition of IL-6.

We therefore examined whether oral ACTH inhibited IL-6 in the GALT, in particular the lamina propria (LP), in the EAE model in vivo thereby decreasing the frequency of Th17 and IFN-γ producing cells and increasing the frequency of Treg cell populations.

2. Materials and methods

Induction of active EAE: C57BL/6 6–8 week old females were actively immunized, maintained, handled and surveiled as outlined previously [30]. Briefly, C57BL/6 6–8 week old females (Jackson Labs, Bar Harbor, ME) were actively immunized by subcutaneous injection (s.c.) of 0.2 ml inoculum containing 200 μg MOG peptide 35–55 (MEVGWYRSPFSRVVHLYRNGK) in IFA (DifcoLabs, Detroit, MI) with 800 μg Mycobacterium tuberculosus hominis H37Ra (MT) on day 0 and 7 [5]. These inoculations were followed with pertussis toxin (PTx) (List Biologicals) 200 ng i.p. on day 0 and day 2. The mice were followed for evidence of disease. Clinical severity was graded daily as follows by a blinded observer: 0 = no disease; 1 = minimal or mild hind limb weakness (associated with limp tail); 2 = moderate hind limb weakness or mild ataxia (waddling gait and/or poor righting ability); 3 = moderate to severe hind limb weakness; 4 = severe hind limb weakness or moderate ataxia; 5 = paraplegia with no more than moderate four limb weakness; 6 = paraplegia with severe four limb weakness or severe ataxia. A mean group clinical score was determined for each treatment arm.

Immuno-active Protein: porcine ACTH (adrenocorticotropic hormone) - Ser-Tyr-Ser-Met-Glu-His-Phe-Arg- Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro-Asp-Ala [Gly]–Gly [Ala]-Glu-Asp-Gln-Ser [Leu]-Ala-Glu-Ala-Phe-Pro-Leu-Glu-Phe) was purchased from Bachem Pharmaceutical, Torrance, CA. Control peptide was scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) (s-MSH) (V-S-P-Y-K-S-G-M-W-E-R-H-F), an end to end mix of the first 13 amino acids of ACTH, the active moiety of ACTH 1–39 that interacts with the melanocortin receptor [31] (provided by the Protein Chemistry Lab Blood Research Institute, Medical College of Wisconsin).

Dosing (feeding) regimen: Once immunized mice attained a clinical score ~ 1, B6 mice were randomized to one of 2 treatment groups and gavaged (fed) with 0.1 ml of 10 μg scrambled peptide (s-MSH) or 10 μg of ACTH daily using a 2.5 cm syringe fitted with a 22–24 gauge ball point needle (Thomas Scientific, Swedesboro, NJ) as previously described [24].

3. Isolation of lamina propria (LP)

3.1. Isolation of LPLs

Mice were euthanized by CO2 asphyxiation followed by cervical dislocation. The small intestine was harvested by cutting 2 cm below stomach, then carefully cutting away connective tissue for the first 5–10 cm. The small intestine was slowly pulled out of the abdomen, cut 1 cm above large intestine, flushed with incomplete media (RPMI: 2% - FBS; 1% - Pen/Strep) using a 18 gauge blunt needle and placed in fresh media (RPMI: 5% FBS). Using glass rod the intestine was pulled up the rod and peyer’s patches (PP) removed. After PP were removed forceps were used to remove any fat on the bottom side of the intestine. Then intestine was sectioned into 5ths. Using a cell scraper, intestinal pieces were scraped to remove residual mucous and feces left in the gut. The intestinal pieces were cut longitudinally, then into ~ 0.5–1 cm pieces, placed into a 15 ml conical tube with 10 ml of incomplete media, inverting the tube several times for cleansing. Intestinal pieces were placed into 20 ml of CMF solution (HBSS; HEPES 10 mM, NaHCO3 25 mM, EDTA 1 mM, DTT 1 mM, 2% FBS), shaken for 30 min at 37 °C and then vortexed for 15 s and wash repeated. EDTA was removed by shaking pieces in complete media for 5 min. Intestinal pieces were added to 10 ml of digestion media (RPMI; FBS 10%, Collagenase D 1 mg/ml, Dispase 0.4 mg/ml, DNase I 0.1 mg/ml), shaken for 1.5 h at 37 °C at 250–300 rpm, vortexed for 15 s, filtered through a cell strainer and rinsed with 5 ml of complete media. Cells were spun and re-suspended in 8 ml of 44% Percoll (1× stock solution: 10× PBS and Percoll; dilute to 44% with RPMI). Five ml of 67% Percoll was added to FBS coated tubes, then 44% Percoll carefully layered over the 67% and spun at 1620 rpm for 20 min. The top layer of gradient carefully was removed, then the cell layer removed and placed in a fresh tube and diluted with more complete media. Cells were spun down, supernatant removed and washed one more time and cells counted.

3.2. Isolation of splenocytes and CNS lymphocytes: see methods in [28]

Cytometry: Lymphocytes were stained with CD4 Rat anti-mouse PE-CF594 (BD BioScience, San Jose, CA), CD4 FITC BioLegend (San Diego, CA), CD11b Rat Anti-mouse/human Rat AF-700 (Biolegend), FoxP3 Rat Anti-mouse PE (eBioscience), T-bet Mouse Anti-mouse PE (BioLegend), IL-17a Rat Anti-mouse PE-Cy7 (BioLegend), IL-17a Rat Anti-mouse Alexa Flour 488 (BD BioScience), IFN-γ Rat Anti-mouse PerCP-Cy5.5 (BD BioScience), IFN-γ Rat Anti-mouse APC-Cy7 (BioLegend), IL-10 Rat Anti-mouse APC (BioLegend), IL-6 Rat Anti-mouse APC (BioLegend) following the manufacturer’s instructions. For phenotypic analysis, FACScan was performed using a Beckman Coulter 10-Color Gallios Flow Cytometer. Specificity of the antibodies was confirmed by isotype-matched control mAb.

3.3. Statistics: statistical analysis was performed using ANOVA and student t-test

(Prism 4.0)

4. Results

We examined the mechanism of action (MOA) of ingested (orally administered) 10 μg ACTH in EAE in the GALT. Mice were immunized and separated into 2 groups once each mouse attained a clinical score ~ 1 (day 15 post immunization) at which time oral dosing was started. The 10 μg s-MSH group increased mean group clinical score and attained a clinical score = 2.7 after 23 days post immunization. The active treatment group showed a significant decrease in group clinical score after initiation of therapy. Ingested 10 μg ACTH shows a significant therapeutic effect (Fig. 1).

Fig. 1.

Fig. 1.

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Ten μg ingested ACTH inhibits clinical EAE attacks. B6 mice (n =8/group) were immunized with MOG peptide 35–55 and were gavaged daily with 0.1 ml of control scrambled peptide (s-MSH) or 10 μg ACTH as described in methods (p < .01, student t, from day 15–23, group clinical score ± SEM). The figure is representative of 3 separate experiments (total n = 32/group).

We next examined the effect of oral ACTH on the frequency of IL-6 producing cells in the GALT. In the lamina propria (LP) immune compartment, CD11b + lymphocytes from ACTH fed mice showed a significant decreased frequency of CD11+ IL-6 cells compared to LP lymphocytes from mice fed s-MSH (Fig. 2). When we looked at Th17 and Th1 producing cells in the LP, there were also significantly less IL-17 and IFNγ producing CD4+ T cells in mice fed ACTH compared to mice fed s-MSH ( Figs. 3 and 4). We also examined for alterations of IL-10 lymphocytes in LP without finding significant differences between ACTH and s-MSH fed mice (data not shown).

Fig. 2.

Fig. 2.

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Oral ACTH decreased the frequency of CD11+ IL-6 cells in LP. Lymphocytes were stained as described in methods. Results are expressed as percentage of cells stained bright for both CD11+ Hi, IL-6. Lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IL-17 cells compared to s-MSH fed control (left) (student t, p < .01). This experiment is representative of 3 separate experiments.

Fig. 3.

Fig. 3.

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Oral ACTH decreased the frequency of CD4+ IL-17 cells in LP. Results are expressed as percentage of cells stained bright for both CD4+ and IL-17a. Lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IL-17 cells compared to s-MSH fed control (left) (student t, p < .01). This experiment is representative of 3 separate experiments.

Fig. 4.

Fig. 4.

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Oral ACTH decreased the frequency of CD4+ IFNγ producing cells in LP. Results are expressed as percentage of cells stained bright for both CD4+ and IFNγ. Lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IFNγ cells compared to s-MSH fed control (left) (student t, p < .05). This experiment is representative of 3 separate experiments.

We next examined the frequency of IL-17/IFNγ producing T cells and Treg lymphocyte subsets affected by oral ACTH treatment in the splenic immune compartment. There was a significant decreased frequency of effector CD4+ IL-17 and CD4 IFNγ T cells in splenocytes from mice fed ACTH compared to mice fed scrambled s-MSH (Figs. 5 and 6). Splenocytes from ACTH fed mice showed a significant increased frequency of CD4 + FoxP3+ cells compared to mice fed s-MSH (Fig. 7). Whole splenocytes showed significant increased IL-10 in mice fed ACTH as opposed to mice fed s-MSH (Fig. 8). However, we were unable to determine the source of the increase IL-10 production within the CD11b or CD19 lymphocyte cell subset (data not shown).

Fig. 5.

Fig. 5.

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Oral ACTH decreased the frequency of CD4+ IL-17 cells in spleen. Results are expressed as percentage of cells stained bright for both CD4+ and IL-17. Lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IL-17 cells compared to s-MSH fed control (left) (student t, p < .03). This experiment is representative of 3 separate experiments.

Fig. 6.

Fig. 6.

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Oral ACTH decreased the frequency of CD4+ IFNγ producing cells in the spleen. Results are expressed as percentage of cells stained bright for both CD4+ and IFNγ. Lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IFNγ cells compared to s-MSH fed control (left) (student t, p < .01). This experiment is representative of 3 separate experiments.

Fig. 7.

Fig. 7.

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Oral ACTH increased the frequency of CD4+ FoxP3 cells in spleen. Results are expressed as percentage of cells stained bright for both CD4+ and FoxP3. Lymphocytes from ACTH fed mice (right) showed increased frequency of CD4+ FoxP3 cells compared to s-MSH fed control (left) (student t, p < .02). This experiment is representative of 3 separate experiments.

Fig. 8.

Fig. 8.

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Oral ACTH increased the frequency of IL-10 producing cells in spleen. Results are expressed as percentage of cells stained bright for both CD45.2 hi, IL-10. Splenocytes from ACTH fed mice (right) showed increased frequency of IL-10 producing cells (6.15) compared to s-MSH fed control (left) (2.48) (student t, p < .03). This experiment is representative of 3 separate experiments.

In the CNS, there was a significant decreased frequency of effector CD4+ IFNγ producing T cells (Fig. 9) and decreased IL-6 lymphocyte in mice fed ACTH compared to mice fed scrambled s-MSH (Fig. 10).

Fig. 9.

Fig. 9.

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Oral ACTH decreased the frequency of CD4+ IFNγ producing T cells in the CNS. Results are expressed as percentage of cells stained bright for both CD4+ and IFNγ. CNS lymphocytes from ACTH fed mice (right) showed decreased frequency of CD4+ IFNγ cells compared to s-MSH fed control (left) (student t, p < .02). This experiment is representative of 3 separate experiments.

Fig. 10.

Fig. 10.

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Oral ACTH decreased the frequency of IL-6 producing lymphocytes in the CNS. Results are expressed as percentage of cells stained bright for both CD45.2 hi, IL-6+. CNS lymphocytes from ACTH fed mice (right) showed decreased frequency of IL-6 producing lymphocytes (10.3) compared to s-MSH fed control (left) (13.0) (student t, p < .05). This experiment is representative of 3 separate experiments.

5. Discussion

Our data shows an overall anti-inflammatory effect of ingested ACTH in MOG immunized mice in the LP, spleen and CNS immune compartments. Most importantly, there was a significant decrease in frequency of IL-6 producing CD11b + lymphocytes and CD4+ IL-17 T cells in mice fed ACTH compared to mice fed control s-MSH. There were also significant decreases in the frequency of splenic MOG induced IL-17 (Teff) and Th1 IFNγ in the ACTH fed group and increased frequency of CD4 + FoxP3+ cells compared to the control s-MSH fed group. The anti-inflammatory effect extended to the CNS with decrease CD4+ IFNγ producing T cells and overall lymphocytic IL-6 producing cells. We also found increased IL-10 producing lymphocytes in the spleen but were unable to establish the source for the increased IL-10.

Therapeutic strategies for multiple sclerosis exacerbations since the 1950s have been based on the use of corticotropin hormone (ACTH) that releases endogenous corticosteroids. Parenteral corticosteroids reduce the inflammatory response by inhibiting lymphocyte proliferation and cell-mediated immune response, down regulate cytokine gene expression and have independent effects on the blood-brain barrier permeability [32,33].

However, corticotropin has direct immunomodulatory effects. Melanocortin (MC) peptides are pro-opiomelanocortin (POMC)-derived amino acid sequences including ACTH (corticotropin) and alpha-MSH [34]. ACTH was one of the first neuropeptides shown to bind to MCR (melanocortin receptors) on lymphocytes and modulate immune responses including IL-6 production [35]. The MC5r is partially responsible for induction of CD25+ CD4+ regulatory T cells [36]. ACTH regulates B6 IFNγ production [37]. We have shown that oral ACTH decreases IL-17 in EAE [28]. Therefore, ACTH could inhibit lymphocyte activation directly via MCR (melanocortin effect) in GALT that is unrelated to stimulation of glucocorticoid release (corticotropin effect) [38,39].

CD11b + DCs are found in the lamina propria and induce high frequencies of T cells producing IL-17 [40]. CD11b + DCs most efficient at inducing Th17 polarization are found at the highest frequency in the duodenum [41]. This is where gavaged ACTH would be primarily deposited (personal observation using methylene blue gavage). This is also true in mesenteric lymph nodes (MLN) where the lack of CD11b + cDCs result in reduced levels of IL-6 [42]. Therefore, the decreased frequency of IL-6 producing CD11b + cells induced by oral ACTH would decrease the frequency of IL-17 producing cells.

Peripheral conversion of CD4+ T cells to Treg cells occurs primarily in gut-associated lymphoid tissue (GALT) [43]. IL-6 is critical in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg) [44]. The decreased frequency of IL-6 producing CD11b + cells by oral ACTH would increase the frequency of Treg cells found in the spleen.

IL-6 can also be an important factor in the development of Th1 IFN-γ producing cells. IL-6 deficiency results in the inhibition of the specific Th1 responses in experimental autoimmune uveitis (EAU) [45]. Depletion of IL-6 reduces the priming of T cells for antigen-specific proliferation and IFN-γ secretion [46]. By inhibiting the frequency of IL-6 producing cells, ingested ACTH can also decrease Th1 IFN-γ producing cells.

We were unable to establish the source for the increased IL-10 from splenic lymphocytes from mice fed with ACTH. Others have shown that dendritic cell populations derived from Peyer’s patches (PP), but not from spleen, produced IL-10 compared with splenic DCs [47,48]. CD11b + populations can induce IL-10 producing naıve T cells [49]. Investigation of naïve T cell populations in spleen will be performed in the future.

Proteins such as ACTH are probably not absorbed after oral administration. However, DCs and lymphocytes in the lamina propria (LP) are situated just beneath a single layer of epithelial cells. CD11b + LP DCs can extend dendrites that interdigitate between neighboring intestinal epithelial cells to sample the intestinal lumen [50]. CD4+ T cells are also in the LP [51]. Both these lymphocytes in the LP have direct contact with polypeptides in the intestinal lumen. ACTH, particularly in the proximal small bowel, would have access to CD4+ T cells and their melanocortin receptors [51,52]. Once LP lymphocytes are activated via MCR by ACTH they can migrate to the MLN and beyond systemically to organs undergoing inflammatory responses [53].

The administration of endogenous immune-active proteins via the gut offers an alternative to systemic application [54] with ease of administration in chronic clinical use [55], patient convenience [56], and would be a great step forward because gut delivery is easy, well tolerated, and inexpensive with a favorable therapeutic index [57,58]. Further clinical trials are planned in MS subjects.

Acknowledgements

The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Landon Dittel provided technical assistance.

Financial support and sponsorship

Quasi Endowmen

Footnotes

Declaration of Competing Interest

There are no financial/commercial conflicts of interests to be disclosed.

Availability of data and materials

Not applicable.

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