Modulation of c-Jun NH2-Terminal (JNK) by Cholinergic Autoantibodies from Patients with Sjögren’s Syndrome
Enri Borda, Daniela Passafaro, Silvia Reina, Leonor Sterin-Borda
DOI: 10.4236/pp.2011.24033   PDF    HTML     5,096 Downloads   8,787 Views   Citations


Background: We wanted to determine (via an immunopharmacological approach) whether the c-Jun NH2 terminal kinase (JNK) cascade is phosphorylated in the submandibular gland by carbachol and cholinergic autoantibodies (IgG) present in the sera of patients with primary Sjögren’s syndrome (pSS) by interaction and activation of salivary gland muscarinic acetylcholine receptors (mAChRs). Methods: The JNK, PGE2 and NOS assays were measured in rat sub- mandibular gland with pSS IgG and carbachol alone or in the presence of different blocker agents. Results: pSS IgG- activated M3 mAChRs stimulated JNK phosphorylation whereas the activation of M1 mAChRs by carbachol stimulated JNK phosphorylation involving calcium-activated mechanism. The intracellular pathway leading to pSS IgG-induced biological effects on JNK activity involved activation of protein kinase C (PKC), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes. Also, activation of COX-2 and COX-1 by pSS IgG and carbachol-induced PGE2 generation were involved. Conclusion: These results may contribute to better understanding the modulatory role of JNK enzymes by cholinergic autoantibodies from pSS patients acting on mAChR in rat submandibular gland.

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E. Borda, D. Passafaro, S. Reina and L. Sterin-Borda, "Modulation of c-Jun NH2-Terminal (JNK) by Cholinergic Autoantibodies from Patients with Sjögren’s Syndrome," Pharmacology & Pharmacy, Vol. 2 No. 4, 2011, pp. 256-265. doi: 10.4236/pp.2011.24033.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] I. Marczinovits, L. Kovacs, A. Gyorgy, G. K. Toth, L. Dorgai, J. A. Molnar, “A peptide of human muscarinic acetylcholine receptor 3 is antigenic in primary Sj?gren’s syndrome”. Journal of Autoimmunity, Vol. 24, 2005, pp. 47-54.
[2] H. M. Moutsopoulos, N. Talal, “Immunologic abnormalities in Sjogren syndrome”. In: Sj?gren’s syndrome: clinical and immunopathological aspects. N. Talal, H. M. Moutsopoulos, editors. Berlín: Springer-Verlag; 1987, pp 258-265.
[3] C. Perez Leiros, L. Sterin-Borda, E. Borda, J. C. Goin, M. M. Hosey, “Desensitization and sequestration of human M3 muscarinic acetylcholine receptors by autoantibodies from patients with Chagas’ disease”. Journal of Biology and Chemeistry Vol. 272, 1999, pp. 12989-12993.
[4] S. Bacman, L. Sterin-Borda, J. J. Camusso, R. Arana, O. Hubscher, E. Borda, “Circulating antibodies against rat parotid gland M3 muscarinic receptors in Sj?gren syndrome”. Clinical Immunology, Vol. 104, 1996, pp. 454- 459.
[5] S. Bacman, A. Berra, L. Sterin-Borda, E. Borda, “Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjogren syndrome”. Investigative Ophthalmology Vision Science, Vol. 42, 2001, pp. 321-327.
[6] S. Reina, L. Sterin-Borda, B. Orman, E. Borda, “Autoantibodies against submandibular gland musdcarinic cholinoceptor subtypes in primary Sjogren syndrome”. European Journal of Inflammation, Vol. 3, 2005, pp. 135-141.
[7] L. Kovacs, I. Marczinovits, A. Gryorgy, G. Toth, L. Dorgai, J. Pal, “Clinical associations of autoantibodies to human muscarinic acetylcholine receptor M3 in primary Sj?gren syndrome”. Rheumatology, Vol. 44, 2005, pp. 1021-1025.
[8] S. Reina, L. Sterin-Borda, B. Orman, E. Borda, “Human mAChR antibodfies from Sjogren syndrome sera increase cerebral nitric oxide synthase activity and nitric oxide synthase mRNA level”. Clinical Immunology, Vol. 113, 2004, pp. 193-202.
[9] S. Reina, B. Orman, L. Anaya, L. Sterin-Borda, E. Borda, “Cholinergic autoantibodies in Sjogren syndrome”. Journal of Dental Research, Vol. 86, 2007, pp. 832-836.
[10] A. Berra, L. Sterin-Borda, S. Bacman, E. Borda, “Role of salivary IgA in the pathogenesis of Sj?gren syndrome”. Clinical Immunology, Vol. 104, 2002, pp. 49-57.
[11] L. J. Dawson, J. Stanbury, N. Venn, B. Hasdimir, S. N. Rogers, P. M. Smith, “Antimuscarinic antibodies in primary Sjogren’s syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells”. Arthritis Rheumatology, Vol. 54, 2006, pp. 1165-1173.
[12] J. Li, Y. M. Ha, N. Y. Ku, S. Y. Choi, S. J. Lee, S. B. Oh, et al. “Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren’s syndrome”. Laboratory Investigation, Vol. 84, 2004, pp.1430-1438.
[13] S. A. Waterman, T. P. Gordon, M. Rischmueller, “Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren’s syndrome”. Arthritis Rheumatology, Vol. 43, 2000, pp. 1647-1654.
[14] S. Cha, E. Singson, J. Cornelius, J. P. Yagna, H. J. Knot, A. B. Peck, “Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sj?gren syndrome-associated autoantibodies”. Journal of Rheumatology, Vol. 33, 2006, pp. 296-306.
[15] D. B. Ferguson, “The flow rate and composition of human labial gland saliva”. Archives of Oral Biology, Vol. 44 (Suppl 1), 1999, pp. S11-S14.
[16] K. Tsubota, M. Kaido, Y. Yagi, T. Fujihara, “Diseases associated with ocular surface abnormalities: the importance of reflex tearing”. British Journal of Ophthalmology, Vol. 83, 1999, pp. 89-91.
[17] R. I. Fox, “Sjogren’s syndrome”. Lancet Vol. 366, 2005, pp. 321-331.
[18] N. Ravald, T. List, “Caries and periodontal conditions in patients with primary Sjogren’s syndrome”. Sweden Dental Journal, Vol. 22, 1998, pp. 97-103.
[19] J. Yuan, A. S. Bowman, M. Aljamali, M. R. Payne, J. S. Tucker, J. W. Dillwith, et al. “Prostaglandin E(2)-stimulated secretion of protein in salivary glands of the lone star tick via a phosphoinositide signaling pathway”. Insect Biochemical Molecular Biology, Vol. 30, 2000, pp. 1099-1106.
[20] G. M. Pasinetti, “Cyclooxygenase and Alzheimer’s disease: implications for preventive initiatives to slow the progression of clinical dementia”, Archives of Gerontology and Geriatric, Vol. 33, 2001, pp. 13-28.
[21] V. Mollage, C. E. Muscoli, E. Masini, S. Cuzzocrea, D. Salvemini, “Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors”. Pharmacological Review, Vol. 57, 2005, pp. 217-252.
[22] S. Ganzinelli, E. Borda, L. Sterin-Borda, “Autoantibodies from schizophrenia patients induce cerebral cox-1/iNOS mRNA expression with NO/PGE2/MMP-3 production”. International Journal of Neuropsychopharmacology, Vol. 13, 2010, pp. 293-303.
[23] E. C. Hulme, N. J. Birdsall, N. J. Buckley, “Muscarinic receptor subtypes”. Annual Review of Pharmacology and Toxicology, Vol. 30, 1990, pp. 633-673.
[24] B. Nicke, K. Detjen, C. D. Logsdon, “Muscarinic cholinergic receptors activate both inhibitory and stimulatory growth mechanisms in NIH3T3 cells”. Journal of Biology and Chemistry, Vol. 274, 1999, pp. 21701-21706.
[25] J. S. Gutkind, K. C. Robbins, “Activation of transforming G protein-coupled receptors induces rapid tyrosine phosphorylation of cellular proteins, including p125FAK and the p130 v-src substrate”. Biochemistry and Biophysic Research Communication, Vol. 188, 1992, pp.155-161.
[26] R. J. Davis, “The mitogen-activated protein kinase signal transduction pathway”. Journal of Biology and Chemistry, Vol. 268, 1993, pp. 14553-14556.
[27] A. Minden, M. Karin, “Regulation and function of the JNK subgroup of MAP kinases”. Biochimistry and Biophysic Acta, Vol. 1333, 1993, pp. F85-F104.
[28] S. Gupta, T. Barrett, A. J. Whitmarsh, J. Cavanagh, H. K. Sluss, B. Dérijard, R. J. Davis, “Selective interaction of JNK protein kinase isoforms with transcription factors”. EMBO Journal, Vol. 15, 1996, pp. 2760-2770.
[29] J. M. Kyriakis, P. Banerjee, E. Nikolakaki, T. Dai, E. A. Rubie, M. F. Ahmad, J. Avruch, J. R. Woodgett. “The stress-activated protein kinase subfamily of c-Jun kinases”. Nature, Vol. 369, 1994, pp. 156-160.
[30] J. M: Kyriakis, J. Avruch, “Sounding the alarm: protein kinase cascades activated by stress and inflammation”. Journal of Biology and Chemistry, Vol. 271, 1996, pp. 24313-24316.
[31] A. Paul, S. Wilson, C. M. Belham, C. J. Robinson, P. H. Scott, G. W. Gould, R. Plevin, “Stress-activated protein kinases: activation, regulation and function”. Cellular Signalling, Vol. 9, 1997, pp. 403-410.
[32] C. A. Dinarello, “Proinflammatory cytokines”. Chest, Vol.118, 2000, pp. 503-508.
[33] J. S. Gutkind, “The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen- activated protein kinase cascades”. Journal of Biology and Chemistry, Vol. 273, 1998, pp. 1839-1842.
[34] O. A. Coso, M. Chiariello, G. Kalinec, J. M. Kyriakis, J. Woodgett, J. S. Gutkind. “Transforming G protein-coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway”. Journal of Biology and Chemistry, Vol. 270, 1995, pp. 5620-5624.
[35] F. M. Mitchell, M. Russell, G. L. Johnson, “Differential calcium dependence in the activation of c-Jun kinase and mitogen-activated protein kinase by muscarinic acetylcholine receptors in rat 1a cells”. Biochemistry Journal, Vol. 309, 1995, pp. 381-384.
[36] O. A. Coso, H. Teramoto, W. F. Simonds, J. S. Gutkind, “Signaling from G protein-coupled receptors to c-Jun kinase involves beta gamma subunits of heterotrimeric G proteins acting on a Ras and Rac1-dependent pathway”. Journal of Biology and Chemistry, Vol. 271, 1996, pp. 3963-3696.
[37] I. E. Zohn, H. Yu, X. Li, A. D. Cox, H. S. Earp, “Angiotensin II stimulates calcium-dependent activation of c-Jun N-terminal kinase”. Molecular Cell Biology, Vol. 15, 1995, pp. 6160-6168.
[38] M. T. Ramirez, V. P. Sah, X. L. Zhao, J. J. Hunter, K. R. Chien, J. H. Brown, “The MEKK-JNK pathway is stimulated by alpha1-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy”. Journal of Biology and Chemistry, Vol. 272, 1997, pp. 14057-14061.
[39] P. S. Shapiro, J. N. Evans, R. J. Davis, J. A. Posada, “The seven-transmembrane-spanning receptors for endothelin and thrombin cause proliferation of airway smooth muscle cells and activation of the extracellular regulated kinase and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases”. Journal of Biology and Chemistry, Vol. 271, 1996, pp. 5750-5754.
[40] M. A. Bogoyevitch, A. J. Ketterman, P. H. Sugden, “Cellular stresses differentially activate c-Jun N-terminal protein kinases and extracellular signal-regulated protein kinases in cultured ventricular myocytes”. Journal of Biology and Chemistry, Vol. 270, 1995, pp. 29710-29717.
[41] A. C. Newton, “Protein kinase C: structure, function, and regulation”. Journal of Biology and Chemistry, Vol. 270, 1995, pp. 28495-28498.
[42] C. Vitali, S. Bombardieri, H. M. Moutsopoulos, G. Balestrieri, W. Bencivelli, R. M. Bernstein, et al. “Preliminary criteria for the classification of Sj?gren’s syndrome. Results from a prospective concerted action supported by the European Community”. Arthritis Rheumatology, Vol. 36, 1993, pp. 340-347.
[43] T. Borda, A. Genaro, L. Sterin-Borda, G. Cremaschi, “Involvement of endogenous nitric oxide signalling system in brain muscarinic acetylcholine receptor activation”. Journal of Neural Transmission, Vol. 105, 1995, pp. 193- 204.
[44] M. P. Caulfield, “Muscarinic receptor characterization, coupling and function”. Pharmacology and Therapeutic, Vol. 58, 1993, pp. 319-379.
[45] M. J. Berridge, “Inositol trisphosphate and calcium signalling”. Nature, Vol. 361, 1993, pp. 315-325.
[46] P. G. Wylie, R. A. Challiss, J. L. Blank, “Regulation of extracellular-signal regulated kinase and c-Jun N-terminal kinase by G-protein-linked muscarinic acetylcholine receptors”. Biochemistry Journal, Vol. 338, 1999, pp. 619- 628.
[47] D. C. Hornigold, R. Mistry, P. D. Raymond, J. L. Blank, R. A. Challiss, “Evidence for cross-talk between M2 and M3 muscarinic acetylcholine receptors in the regulation of second messenger and extracellular signal-regulated kinase signalling pathways in Chinese hamster ovary cells”. Brithis Journal of Pharmacology, Vol. 138, 2003, pp. 1340-1350.
[48] P. Kubes, D. M. McCafferty, “Nitric oxide and intestinal inflammation”. American Journal of Medicine, Vol. 109, 2000, pp. 150-118.
[49] M. T. Heneka, D. L. Feinstein, “Expression and function of inducible nitric oxide synthase in neurons”. Journal of Neuroimmunology, Vol. 114, 2001, pp. 8-18.
[50] D. Zoukhri, E. Macari, S. H. Choi, C. L. Kublin, “c-Jun NH2-terminal kinase mediates interleukin-1beta-induced inhibition of lacrimal gland secretion”. Journal of Neurochemistry, Vol. 96, 2006, pp. 126-135.
[51] K. Soejima, H. Nakamura, M. Tamai, A. Kawakami, K. Eguchi, “Activation of MKK4 (SEK1), JNK, and c-Jun in labial salivary infiltrating T cells in patients with Sj?gren’s syndrome”. Rheumatology Inernational, Vol. 27, S.
[52] S. Gonzalo, L. Grasa, M. P. Arrueba, M. A. Plaza, M. D. Murillo, “Lipopolysaccharide-induced digestive and liver disease”. Digestive and Liver Disease, Vol. 43, 2011, pp. 277-285.

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