Abstract
Accumulating evidence indicates that the neuropeptide substance P (SP) is predominantly involved in neurogenic inflammation and pain perception via its high-affinity neurokinin 1 receptor (NK-1R). Intriguingly, decreased pain sensitivity is found to be associated with high plasma progesterone levels. We hypothesize that progesterone may attenuate nociception and associated inflammatory response via NK-1R-dependent pathways. To address our hypothesis, we incubated splenic lymphocytes from CBA/J female mice with different concentrations of the progesterone derivative dydrogesterone. Subsequently, the expressions of NK-1R and T helper (Th1)-type cytokines were analyzed by flow cytometry. Next, we subcutaneously injected CBA/J mice with 1.25 mg of dydrogesterone in 200-μl sesame oil; control mice were sham-injected. Tail flick test to detect the nociceptive threshold was performed in 30-min intervals upon injection. Lymphocytes were isolated from blood and uterus and analyzed for NK-1R surface expression. Immunohistochemical analyses were performed to investigate the uterine tissue distribution of NK-1R. Dydrogesterone induced a decrease in the percentage of NK-1R+ lymphocytes in vitro and in vivo. Additionally, an increase in Th2-type and a decrease in Th1-type cytokines could be detected in vitro after incubation with dydrogesterone. An increased tail flick latency following dydrogesterone injection supported the concept that decreased expression of the NK-1R on lymphocytes is associated with an increased pain threshold. Taken together, these results clearly reveal a pathway by which dydrogesterone or progesterone respectively modulates the cross talk of the nervous, endocrine and immune systems in inflammation and pain.
Similar content being viewed by others
Abbreviations
- Th:
-
(T helper)
- IL:
-
Interleukin
- SP:
-
Substance P
- NK-1R:
-
Neurokinin 1 receptor
References
Vitetta ES, Berton MT, Burger C, Kepron M, Lee WT, Yin XM (1991) Memory B and T cells. Annu Rev Immunol 9:193–217
De Kloet ER (2004) Hormones and the stressed brain. Ann N Y Acad Sci 1018:1–15
O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F (2004) The role of substance P in inflammatory disease. J Cell Physiol 201:167–180
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638
Licinio J, Frost P (2000) The neuroimmune–endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus–pituitary–adrenal hormone dynamics. Braz J Med Biol Res 33:1141–1148
Brazzini B, Ghersetich I, Hercogova J, Lotti T (2003) The neuro–immuno–cutaneous–endocrine network: relationship between mind and skin. Dermatol Ther 16:123–131
Zhu C, Liu Q, Wei Y, Ma C, Hao J, Yan P (1999) Coexistence of immune–neuro–endocrine substances in the rat central neurons. J Tongji Med Univ 19:81–85
Dhabhar FS (2003) Stress, leukocyte trafficking, and the augmentation of skin immune function. Ann N Y Acad Sci 992:205–217
Beishuizen A, Thijs LG (2003) Endotoxin and the hypothalamo–pituitary–adrenal (HPA) axis. J Endotoxin Res 9:3–24
Haddad JJ, Saade NE, Safieh-Garabedian B (2002) Cytokines and neuro–immune–endocrine interactions: a role for the hypothalamic–pituitary–adrenal revolving axis. J Neuroimmunol 133:1–19
Corcos M, Guilbaud O, Hjalmarsson L, Chambry J, Jeammet P (2002) Cytokines and depression: an analogic approach. Biomed Pharmacother 56:105–110
Espinosa E, Bermudez-Rattoni F (2001) Behavior–immunity relationship: the role of cytokines. Rev Invest Clin 53:240–253
Sakane T, Suzuki N (2000) Neuro–endocrine–immune axis in human rheumatoid arthritis. Arch Immunol Ther Exp (Warsz) 48:417–427
Mazzoccoli G, Correra M, Bianco G, De Cata A, Balzanelli M, Giuliani A, Tarquini R (1997) Age-related changes of neuro–endocrine–immune interactions in healthy humans. J Biol Regul Homeost Agents 11:143–147
Anisman H, Baines MG, Berczi I, Bernstein CN, Blennerhassett MG, Gorczynski RM, Greenberg AH, Kisil FT, Mathison RD, Nagy E, Nance DM, Perdue MH, Pomerantz DK, Sabbadini ER, Stanisz A, Warrington RJ (1996) Neuroimmune mechanisms in health and disease: 2. Disease. CMAJ 155: 1075–1082
Besedovsky HO, del Rey A (1992) Immune–neuroendocrine circuits: integrative role of cytokines. Front Neuroendocrinol 13:61–94
Weihe E, Nohr D, Michel S, Muller S, Zentel HJ, Fink T, Krekel J (1991) Molecular anatomy of the neuro–immune connection. Int J Neurosci 59:1–23
Dorner G (1989) Hormone-dependent brain development and neuroendocrine prophylaxis. Exp Clin Endocrinol 94:4–22
Baulieu E, Schumacher M (2000) Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Steroids 65:605–612
Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, Luger TA, Hollenberg MD (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 26:1–43
Liddle RA, Nathan JD (2004) Neurogenic inflammation and pancreatitis. Pancreatology 4:551–559
Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T (2003) Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 139:1479–1488
Maggi CA (1995) Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog Neurobiol 45:1–98
Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82:981–1011
Laird JM, Olivar T, Roza C, De Felipe C, Hunt SP, Cervero F (2000) Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98:345–352
Adcock IM, Peters M, Gelder C, Shirasaki H, Brown CR, Barnes PJ (1993) Increased tachykinin receptor gene expression in asthmatic lung and its modulation by steroids. J Mol Endocrinol 11:1–7
Goode T, O'Connor T, Hopkins A, Moriarty D, O'Sullivan GC, Collins JK, O'Donoghue D, Baird AW, O'Connell J, Shanahan F (2003) Neurokinin-1 receptor (NK-1R) expression is induced in human colonic epithelial cells by proinflammatory cytokines and mediates proliferation in response to substance P. J Cell Physiol 197:30–41
Quartara L, Maggi CA (1998) The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles. Neuropeptides 32:1–49
Heppelmann B, Pawlak M (1997) Sensitisation of articular afferents in normal and inflamed knee joints by substance P in the rat. Neurosci Lett 223:97–100
Baker ME (1997) Steroid receptor phylogeny and vertebrate origins. Mol Cell Endocrinol 135:101–107
Melcangi RC, Cavaretta IT, Ballabio M, Leonelli E, Schenone A, Azcoitia I, Miguel Garcia-Segura L, Magnaghi V (2005) Peripheral nerves: a target for the action of neuroactive steroids. Brain Res Brain Res Rev 48(2):328–338
Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H (1999) Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 51(1):63–81
Schumacher M, Akwa Y, Guennoun R, Robert F, Labombarda F, Desarnaud F, Robel P, De Nicola AF, Baulieu EE (2000) Steroid synthesis and metabolism in the nervous system: trophic and protective effects. J Neurocytol 29(5–6):307–326
Miyaura H, Iwata M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168:1087–1094
Moro MH, Bjornsson J, Marietta EV, Hofmeister EK, Germer JJ, Bruinsma E, David CS, Persing DH (2001) Gestational attenuation of Lyme arthritis is mediated by progesterone and IL-4. J Immunol 166:7404–7409
Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2003) Classification and pharmacology of progestins. Maturitas 46 (Suppl 1):S7–S16
Arck PC, Merali FS, Manuel J, Chaouat G, Clark DA (1995) Stress-triggered abortion: inhibition of protective suppression and promotion of tumor necrosis factor-alpha (TNF-alpha) release as a mechanism triggering resorptions in mice. Am J Reprod Immunol 33:74–80
Franke HR, Kole S, Ciftci Z, Haanen C, Vermes I (2003) In vitro effects of estradiol, dydrogesterone, tamoxifen and cyclophosphamide on proliferation vs. death in human breast cancer cells. Cancer Lett 190:113–118
Blois SM, Joachim R, Kandil J, Margni R, Tometten M, Klapp BF, Arck PC (2004) Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile. J Immunol 172:5893–5899
Joachim R, Zenclussen AC, Polgar B, Douglas AJ, Fest S, Knackstedt M, Klapp BF, Arck PC (2003) The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response. Steroids 68:931–940
Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53:597–652
Blois SM, Alba Soto CD, Tometten M, Klapp BF, Margni RA, Arck PC (2004) Lineage, maturity, and phenotype of uterine murine dendritic cells throughout gestation indicate a protective role in maintaining pregnancy. Biol Reprod 70:1018–1023
Silverman AJ, Sutherland AK, Wilhelm M, Silver R (2000) Mast cells migrate from blood to brain. J Neurosci 20:401–408
van der Kleij HP, Ma D, Redegeld FA, Kraneveld AD, Nijkamp FP, Bienenstock J (2003) Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol 171:2074–2079
Joachim RA, Hildebrandt M, Oder J, Klapp BF, Arck PC (2001) Murine stress-triggered abortion is mediated by increase of CD8+ TNF-alpha+ decidual cells via substance P. Am J Reprod Immunol 45:303–309
Marx L, Arck P, Kapp M, Kieslich C, Dietl J (1999) Leukocyte populations, hormone receptors and apoptosis in eutopic and ectopic first trimester human pregnancies. Hum Reprod 14:1111–1117
Tharp MD, Seelig LL, Jr., Tigelaar RE, Bergstresser PR (1985) Conjugated avidin binds to mast cell granules. J Histochem Cytochem 33:27–32
Ihara H, Nakanishi S (1990) Selective inhibition of expression of the substance P receptor mRNA in pancreatic acinar AR42J cells by glucocorticoids. J Biol Chem 265:22441–22445
Pinto FM, Armesto CP, Magraner J, Trujillo M, Martin JD, Candenas ML (1999) Tachykinin receptor and neutral endopeptidase gene expression in the rat uterus: characterization and regulation in response to ovarian steroid treatment. Endocrinology 140:2526–2532
Candenas ML, Magraner J, Armesto CP, Anselmi E, Nieto PM, Martin JD, Advenier C, Pinto FM (2001) Changes in the expression of tachykinin receptors in the rat uterus during the course of pregnancy. Biol Reprod 65:538–543
Bradesi S, Eutamene H, Garcia-Villar R, Fioramonti J, Bueno L (2003) Stress-induced visceral hypersensitivity in female rats is estrogen-dependent and involves tachykinin NK1 receptors. Pain 102:227–234
Kincy-Cain T, Bost KL (1997) Substance P-induced Il-12 production by murine macrophages. J Immunol 158(5):2334–2339
Blum AM, Metwali A, Elliott DE, Weinstock JV (2003) T cell substance P receptor governs antigen-elicited IFN-gamma production. Am J Physiol Gastrointest Liver Physiol 284(2):G197–204
Weinstock JV, Blum A, Metwali A, Elliott D, Bunnett N, Arsenescu R (2003) Substance P regulates Th1-type colitis in IL-10 knockout mice. J Immunol 171(7):3762–3767
Coirini H, Gouezou M, Liere P, Delespierre B, Pianos A, Eychenne B, Schumacher M, Guennoun R (2002) 3 Beta-hydroxysteroid dehydrogenase expression in rat spinal cord. Neuroscience 113(4):883–891
Patte-Mensah C, Kappes V, Freund-Mercier MJ, Tsutsui K, Mensah-Nyagan AG (2003) Cellular distribution and bioactivity of the key steroidogenic enzyme, cytochrome P450 side chain cleavage, in sensory neural pathways. J Neurochem 86(5):1233–1246
Patte-Mensah C, Penning TM, Mensah-Nyagan AG (2004) Anatomical and cellular localization of neuroactive 5 alpha/3 alpha-reduced steroid-synthesizing enzymes in the spinal cord. J Comp Neurol 477(3):286–299
Kibaly C, Patte-Mensah C, Mensah-Nyagan AG (2005) Molecular and neurochemical evidence for the biosynthesis of dehydroepiandrosterone in the adult rat spinal cord. J Neurochem 93(5):1220–1230
Patte-Mensah C, Kibaly C, Mensah-Nyagan AG (2005) Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: a potential component of nociception. Proc Natl Acad Sci U S A 102(25):9044–9049
Mertz PM, DeWitt DL, Stetler-Stevenson WG, Wahl LM (1994) Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. J Biol Chem 269:21322–21329
Poole S, Cunha FQ, Selkirk S, Lorenzetti BB, Ferreira SH (1995) Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10. Br J Pharmacol 115:684–688
Acknowledgements
The authors would like to thank Evi Hagen, Petra Moschansky, Petra Busse and Bori Handjinski for their excellent technical assistance and continuous support in generating this work. Sandra Blois and Petra Arck are part of the EMBIC Network of Excellence, co-financed by the European Commission throughout the FP6 framework program ‘Life Science, Genomics and Biotechnology for Health’. Arif Orsal is supported by fellowships of Turkish Higher Education Council. Sandra Blois is a fellow of the Ernst Schering Foundation. This work was further made possible by research grants from the Charité to Arif Orsal and Petra Arck.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Orsal, A.S., Blois, S., Labuz, D. et al. The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice. J Mol Med 84, 159–167 (2006). https://doi.org/10.1007/s00109-005-0005-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-005-0005-5