Peripheral cytokines profile in Parkinson’s disease

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Abstract

Higher levels of proinflammatory cytokines are found in Parkinson’s disease (PD) patient’s brains and inflammation is thought to be a major contributor to the neurodegeneration. During the inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood–brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines [Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinson’s disease, Br. J. Pharmacol. 50, 963–976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood–brain barrier dysfunction in parkinsonian midbrain in vivo, Ann. Neurol. 57, 176–179]. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain.

Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients.

Basal and LPS-induced levels of MCP-1, RANTES, MIP-1α, IL-8, IFNγ, IL-1β and TNFα were significantly higher in PD patients than in HC subjects (p < 0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage (p < 0.001). The Pearson’s correlation coefficient (R) was also used to assess the strength of the relationship between NF-κBp65 levels and all studied cyto/chemokines and between NF-κBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.

Introduction

Parkinson disease (PD),1 a common neurological disorder in the elderly, is characterized by resting tremor, bradykinesia, muscular rigidity. The progressive and massive loss of midbrain dopaminergic neurons is considered a pathological hallmark of the disease. The origin of this neuronal degeneration is unknown and may involve several molecular and cellular events, including oxidative stress, accumulation of altered proteins, excitotoxicity, proapoptotic mechanisms and mitochondrial dysfunction (Dauer and Przedborski, 2003, Hald and Lotharius, 2005). One hypothesis concerning the cause of degeneration of the nigrostriatal dopaminergic neurons is that PD is caused by programed cell death (apoptosis) due to increased levels of cytokines, apoptosis-related proteins and/or to decreased levels of neurotrophins. Several studies have reported increases and decreases in the levels of proinflammatory cytokines and neurotrophins in the brain of PD patients, thus suggesting that neuroinflammation and apoptosis may contribute to the pathogenesis of PD (Nagatsu and Sawada, 2005, Sawada et al., 2006, McGeer et al., 1988, McGeer and McGeer, 2004, Tansey et al., 2007, Tansey et al., 2008). Epidemiological evidence suggests an association between neuroinflammation and PD (Whitton, 2007) with a previous study presenting findings in which inflammatory gene cytokine polymorphisms of TNFα and IL-1β increase risk of PD (Wahner et al., 2007). Higher levels of TNFα, (interleukin) IL-1β, IL-2, IL-4, IL-6, transforming growth factor-α (TGFα), and transforming growth factor-β1 (TGFβ1) and β2 (TGFβ2) have also been detected by several investigators in the brain parenchyma or cerebrospinal fluid of PD patients. Furthermore, activation of the transcription factor nuclear factor kappa B (NF-κB), that controls target genes encoding proinflammatory cytokines, adhesion molecules, chemokines, growth factors and inducible enzymes, is also seen in PD brain (Mogi et al., 2007). A small number of CD8-positive T-lymphocytes in the vicinity of degenerating neurons (McGeer et al., 1988) and an higher density of interferon-γ-positive cells in the CNS of patients with PD compatible with the presence of lymphocytes (Hunot et al., 1999) suggest that an infiltration of immune cells across the blood–brain barrier may also participate in the pathophysiology of the disease.

Interestingly, immune activation in neurodegenerative diseases is not restricted to brain sites (Singh and Guthikonda, 1997, Chen et al., 2008), and abnormalities in peripheral immune functions in patients with Parkinson’s disease (PD) such as changes in lymphocytic subpopulations in the blood and cerebrospinal fluid, deviation of T-lymphocyte subset, impaired production of interleukin2 (IL-2) and higher production of IFNγ by PBMC as well as plasma elevations of some cytokines have been reported by several authors (Hisanaga et al., 2001, Orr et al., 2002, Stypula et al., 1996, Dobbs et al., 1999, Bongiovanni et al., 1997). Taken together, this data suggests that the microenvironment of the central and peripheral immunologic system is modified in PD during the pathological process, although it is not clear if these changes are secondary to the process of cell degeneration, or if they may be playing an active role in neurodegeneration. Change in the brain could affect immune cells in vivo and these effects could be transferred to the peripheral immune system (Kortekaas et al., 2005).

The question of the existence of a systemic inflammation in PD, of which cytokines may be possibly involved in this phenomenon, might be relevant to clinicians in order to better understand the pathophysiology of this common disease. The aim of the present study was to investigate whether the PD is associated with increased cytokine and/or chemokines production by peripheral blood mononuclear cells (PBMC). Our data show that in PD patient’s production of selected proinflammatory cyto/chemokine was higher than in healthy controls focusing the possibility that peripheral blood mononuclear cells (PBMCs) produce a broad range of proinflammatory cytokines/chemokines influencing each other and forming a cytokine network. As these molecular modulators of inflammation are controlled by transcription factor NF-κB, we determined the NF-κB activation in PD and, more generally the role of peripheral immune activation in idiopathic PD.

Section snippets

Patients and controls

Patients with a diagnosis of idiopathic PD consistent with UK BBC (Hughes et al., 1992) clinical criteria were considered appropriate for enrolment. All the 40 included PD patients were consecutively recruited in Movement Disorder Clinic of University of Chieti. The mean age was 64.7 ± 8.9 years and the mean duration of illness at time of enrolment was 10.7 ± 5.9 years. All patients underwent Mini-Mental State Examination (MMSE) (Folstein et al., 1975). H/Y (Hoehn and Yahr, 1967) stage was between

Chemokines Production

In order to investigate a possible involvement of MCP-1, RANTES, MIP-1α and IL-8 in PD, the production of these chemokines by PBMC was evaluated. Table 2 summarizes the mean (±standard deviation) values of chemokines detected in cell-free supernatants of PBMC from PD patients and HC subjects group. PBMC from two groups of subjects constitutively produced detectable amounts of IL-8, MCP-1, RANTES and MIP-1α. Significantly higher levels of IL-8, MCP-1 and MIP-1α were detected in PD patients

Discussion

Elevated inflammatory cytokines in the brain, cerebral spinal fluid (CSF) and plasma of PD patients supports the existence of functional interconnections between the immune and nervous systems. (Koprich et al., 2008, Mogi et al., 1996a, Mogi et al., 1996b, Baba et al., 2005, Selikhova et al., 2002, Bessler et al., 1999).

To investigate whether the increased peripheral cytokine and/or chemokines production is associated with PD we have utilized an experimental model based on an “in vitro” study

Acknowledgments

We thank Renato Barbacane for his cheerful assistance with the preparation of the manuscript, and all members of our laboratory for their advice and encouragement.

This research was supported by grants from the Italian MIUR (60%, 2006).

References (54)

  • C. Iarlori et al.

    RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients treated with interferon-beta-1b

    J. Neuroimmunol.

    (2000)
  • L. Matera et al.

    Communication of the central nervous and the immune systems

    J. Neuroimmunol.

    (2000)
  • P.L. McGeer et al.

    Inflammation and neurodegeneration in Parkinson’s disease

    Parkinsonism Relat. Disord.

    (2004)
  • P.L. McGeer et al.

    The alpha-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease

    Exp Neurol.

    (2008)
  • M. Mogi et al.

    Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease

    Neuroscience

    (1996)
  • M. Mogi et al.

    p53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain

    Neurosci. Lett.

    (2007)
  • N. Mukaida et al.

    Cooperative interaction of nuclear factor kappa B and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines

    J. Biol. Chem.

    (1990)
  • C.F. Orr et al.

    An inflammatory review of Parkinson’s disease

    Prog. Neurobiol.

    (2002)
  • M. Reale et al.

    Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines

    J. Neuroimmunol.

    (2004)
  • M. Reale et al.

    Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer’s disease patients

    Exp. Gerontol.

    (2005)
  • V.K. Singh et al.

    Circulating cytokines in Alzheimer’s disease

    J. Psychiatr. Res.

    (1997)
  • M.G. Tansey et al.

    Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention

    Exp. Neurol.

    (2007)
  • S.E. Walker et al.

    Roles of prolactin and gonadotropin-releasing hormone in rheumatic diseases

    Rheum. Dis. Clin. North Am.

    (2000)
  • X.H. Zhu et al.

    Effects of prolactin and metoclopramide on macrophage cytokine gene expression in late sepsis

    Cytokine

    (1997)
  • A.S. Baldwin

    Series introduction: the transcription factor NF-κB and human disease

    J. Clin. Invest.

    (2001)
  • P. Bongiovanni et al.

    T-lymphocyte immune-interferon binding in parkinsonian patients

    J. Neural Transm.

    (1997)
  • A. Boyum

    Separation of blood leucocytes, granulocytes and lymphocytes

    Tissue Antigens

    (1974)
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