HyrSelf Functional Medicine What are the effects of Estradiol (E2) on stimulating the following Th1 cytokines: IL-2, IL-12, IL-21, IL-36α, INF-ƴ, TNF-α

What are the effects of Estradiol (E2) on stimulating the following Th1 cytokines: IL-2, IL-12, IL-21, IL-36α, INF-ƴ, TNF-α

β-estradiol (E2) treatment exacerbates the severity of systemic lupus erythematosus and myasthenia gravis.1Engelmann F, Rivera A, Park B, Messerle-Forbes M, Jensen JT, Messaoudi I. Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women. PLoS One. 2016 Feb 9;11(2):e0149045.,2Carlsten H, Nilsson N, Jonsson R, Backman K, Holmdahl R, Tarkowski A (1992) Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune. MRL lpr/lpr mice. Cell Immunol 144: 190–202.,3Delpy L, Douin-Echinard V, Garidou L, Bruand C, Saoudi A, Guery JC (2005) Estrogen enhances susceptibility to experimental autoimmune myasthenia gravis by promoting type 1-polarized immune responses. J Immunol 175: 5050–5057.

On the other hand, the severity and incidence of rheumatoid arthritis and multiple sclerosis are decreased during pregnancy [3] when suppression of the immune system by circulating levels of progesterone, estradiol (E3) and estetrol (E4) are high.4Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.

Cytokine production by peripheral blood T cells varies throughout the menstrual cycle. Specifically, the number of PBMC able to secrete IL-4 in response to stimulation correlated with estrogen levelsVerthelyi 5D, Klinman DM (2000) Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology 100: 384–390. and serum levels of the cytokines IL-6, IL-1β, IL-10, and IL-8 peak during the follicular phase when estrogen levels are highest.6Angstwurm MW, Gartner R, Ziegler-Heitbrock HW (1997) Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine 9: 370–374.,7Al-Harthi L, Wright DJ, Anderson D, Cohen M, Matity Ahu D, Cohn J, et al. (2000) The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J Interferon Cytokine Res 20: 719–724.,8Franklin RD, Kutteh WH (1999) Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones. J Reprod Immunol 42: 93–106.

Estradiol (E2) can directly Influence lymphocyte function. B cells exposed to Estradiol (E2) increases: 1) the expression of Bcl-2, which is over-expressed in many tumors and contributes to tumor growth, progression, and resistance to therapy.9Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI (1998) Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 25: 1305–1312.,10Verthelyi DI, Ahmed SA (1998) Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Cell Immunol 189: 125–134.,11Rider V, Jones S, Evans M, Bassiri H, Afsar Z, Abdou NI (2001) Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 28: 2644–2649.,12Evans MJ, MacLaughlin S, Marvin RD, Abdou NI (1997) Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNFalpha production in SLE but not in normal cultures. Clin Immunol Immunopathol 82: 258–262.; 2) B cell activation;13Paavonen T, Andersson LC, Adlercreutz H (1981) Sex hormone regulation of in vitro immune response. Estradiol enhances human B cell maturation via inhibition of suppressor T cells in pokeweed mitogen stimulated cultures. J Exp Med 154: 1935–1945. 3) increased IgG production;14Kanda N, Tamaki K (1999) Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol 103: 282–288. and 4) increased diversity of antibodies with a high-affinity of autoantibodies causing tissue injury by forming complexes with antigens15Karpuzoglu E, Zouali M (2009) The multi-faceted influences of estrogen on lymphocytes: toward novel immuno-interventions strategies for autoimmunity management. Clin Rev Allergy Immunol 40: 16–26. leading to increased antibody diversity happening at a significantly higher rate than normal, leading to a potential for producing antibodies with altered binding affinities and impacting immune response function.16Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.

Similarly, E2 was shown to inhibit activation-induced apoptosis of T cells from lupus patients by down-regulating the expression of Fas ligand.17Kim WU, Min SY, Hwang SH, Yoo SA, Kim KJ, Cho CS (2010) Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol 161: 453–458. Estradiol (E2) promotes a potential immune system bias towards Th2, Th17, and Treg polarization.18Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 84: 370–378.,19Khan D, Dai R, Karpuzoglu E, Ahmed SA (2010) Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice. Eur J Immunol 40: 2549–2556. Estrogen and progesterone can also indirectly influence T and B cells by affecting the function of innate immune cells such as dendritic cells and macrophages that influence T and B cell differentiation.20Kovats S, Carrera E, Agarwal H (2010) Sex Steroid receptors in Immune Cells. In: Klein SL, Roberts CW, editors. Sex Hormones and Immunity to Infection. Berlin: Springer. pp. 53–91. In contrast, estradiol treatment increases the ability of macrophages to secrete inflammatory cytokines.21Calippe B, Douin-Echinard V, Delpy L, Laffargue M, Lelu K, Krust A, et al. (2010) 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol 185: 1169–1176.,22Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.

Explore how sex hormones like testosterone and estradiol influence cytokine production, including IL-2, IL-12, IL-21, IL-36α, INF-γ, and TNF-α. Learn how testosterone generally suppresses immune responses, while estradiol can either enhance or inhibit these cytokines based on its concentration and context.

All Sex hormones can modulate the immune system, including the production of various Th1 cytokines such as IL-2, IL-12, IL-21, IL-36α, INF-γ, and TNF-α. Be aware that researchers will use the word “stimulate” ambiguously. For example they may claim a hormone stimulates suppression of the immune system. For example, Testosterone stimulates suppression of the Th1 Immune System. They somehow omit the word “Suppress”. In other studies, they will report that a cytokine is “Anti-Inflammatory”, another word for “Suppression of the Immune System”.

Be Wary of the term: Anti-Inflammatory

Be wary of the term “Anti-Inflammatory”.

For example, IL 10 (a Th2 cytokine) is used interchangably with the word “Anti-Inflammatory” in many studies. However, high levels of IL10 cytokines cause Anaphylactic shock, a severe life threatening immune response. These same researchers will report their bewilderment on how they are finding high levels of the “Anti-Inflammatory” IL 10 in people experiencing an Anaphylactic reaction. They are incapable of thinking in terms of hormones, neurotransmitters or cytokines being dose-dependent.

Melatonin is Dose Dependent. Researchers and Influencers only look at the effects of Low melatonin levels.

Th1 Cytokines

Below is how sex hormones generally influence these cytokines:

Interleukin-2 (IL-2):

  • Testosterone: Suppresses IL-2 production. Testosterone has immunosuppressive effects, reducing T cell proliferation and IL-2 secretion.
  • Estradiol: Can enhance IL-2 production in certain contexts, particularly at low-to-moderate concentrations, promoting T cell activation.

Interleukin-12 (IL-12):

  • Testosterone: Tends to suppress IL-12 production, contributing to a reduced Th1 response (associated with inflammation).
  • Estradiol: At lower concentrations, estradiol can stimulate IL-12 production, supporting Th1 responses, but higher concentrations may have the opposite effect.

Interleukin-21 (IL-21):

  • Testosterone: Inhibits IL-21 production, which is key in regulating immune cell functions such as B cell differentiation and T follicular helper cells.
  • Estradiol: May enhance IL-21 secretion, helping with the regulation of immune responses, particularly in adaptive immunity.

Interleukin-36α (IL-36α):

  • Testosterone: The effect on IL-36α is not well-documented, but given testosterone’s overall immunosuppressive nature, it might reduce IL-36α production.
  • Estradiol: The effect of estradiol on IL-36α is not fully understood, though Estradiol generally supports pro-inflammatory cytokine production at lower doses.

Interferon-gamma (INF-γ):

  • Testosterone: Suppresses INF-γ production, reducing Th1 responses and overall immune activation.
  • Estradiol: At low-to-moderate levels, estradiol promotes INF-γ secretion, enhancing the Th1 response. However, higher levels of estradiol can have an inhibitory effect.

Tumor Necrosis Factor-alpha (TNF-α):

  • Testosterone: Inhibits TNF-α production, contributing to anti-inflammatory effects.
  • Estradiol: Can increase TNF-α production at certain levels, but its effect can be complex, as estradiol also modulates inflammation in a context-dependent manner.

Overall, testosterone generally has an immunosuppressive effect on these cytokines, reducing inflammatory responses. Estradiol, depending on its concentration and the immune context, can either enhance or inhibit the production of these cytokines.

References

  • 1
    Engelmann F, Rivera A, Park B, Messerle-Forbes M, Jensen JT, Messaoudi I. Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women. PLoS One. 2016 Feb 9;11(2):e0149045.
  • 2
    Carlsten H, Nilsson N, Jonsson R, Backman K, Holmdahl R, Tarkowski A (1992) Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune. MRL lpr/lpr mice. Cell Immunol 144: 190–202.
  • 3
    Delpy L, Douin-Echinard V, Garidou L, Bruand C, Saoudi A, Guery JC (2005) Estrogen enhances susceptibility to experimental autoimmune myasthenia gravis by promoting type 1-polarized immune responses. J Immunol 175: 5050–5057.
  • 4
    Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.
  • 5
    D, Klinman DM (2000) Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology 100: 384–390.
  • 6
    Angstwurm MW, Gartner R, Ziegler-Heitbrock HW (1997) Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine 9: 370–374.
  • 7
    Al-Harthi L, Wright DJ, Anderson D, Cohen M, Matity Ahu D, Cohn J, et al. (2000) The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J Interferon Cytokine Res 20: 719–724.
  • 8
    Franklin RD, Kutteh WH (1999) Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones. J Reprod Immunol 42: 93–106.
  • 9
    Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI (1998) Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 25: 1305–1312.
  • 10
    Verthelyi DI, Ahmed SA (1998) Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Cell Immunol 189: 125–134.
  • 11
    Rider V, Jones S, Evans M, Bassiri H, Afsar Z, Abdou NI (2001) Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 28: 2644–2649.
  • 12
    Evans MJ, MacLaughlin S, Marvin RD, Abdou NI (1997) Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNFalpha production in SLE but not in normal cultures. Clin Immunol Immunopathol 82: 258–262.
  • 13
    Paavonen T, Andersson LC, Adlercreutz H (1981) Sex hormone regulation of in vitro immune response. Estradiol enhances human B cell maturation via inhibition of suppressor T cells in pokeweed mitogen stimulated cultures. J Exp Med 154: 1935–1945.
  • 14
    Kanda N, Tamaki K (1999) Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol 103: 282–288.
  • 15
    Karpuzoglu E, Zouali M (2009) The multi-faceted influences of estrogen on lymphocytes: toward novel immuno-interventions strategies for autoimmunity management. Clin Rev Allergy Immunol 40: 16–26.
  • 16
    Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.
  • 17
    Kim WU, Min SY, Hwang SH, Yoo SA, Kim KJ, Cho CS (2010) Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol 161: 453–458.
  • 18
    Polanczyk MJ, Hopke C, Vandenbark AA, Offner H (2006) Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 84: 370–378.
  • 19
    Khan D, Dai R, Karpuzoglu E, Ahmed SA (2010) Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice. Eur J Immunol 40: 2549–2556.
  • 20
    Kovats S, Carrera E, Agarwal H (2010) Sex Steroid receptors in Immune Cells. In: Klein SL, Roberts CW, editors. Sex Hormones and Immunity to Infection. Berlin: Springer. pp. 53–91.
  • 21
    Calippe B, Douin-Echinard V, Delpy L, Laffargue M, Lelu K, Krust A, et al. (2010) 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol 185: 1169–1176.
  • 22
    Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339: 285–291.