Molecular Mechanisms for α2-Adrenoceptor-Mediated Regulation of Synoviocyte Populations

Mishima, Katsuyuki; Otani, Hitomi; Tanabe, Takatoshi; Kawasaki, Hiroshi; Oshiro, Akihiro; Saito, Naoaki; Ogawa, Ryokei; Inagaki, Chiyoko

doi:10.1254/jjp.85.214

Cited by 19 publications

(8 citation statements)

References 40 publications

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“…Expression of the adrenergic, alpha-2A-, receptor (ADRA2A) increased 14.4-fold in RASFs. The adrenergic, alpha-2A-, receptor may play a critical role in the proliferation and differentiation of synoviocytes [29]. Although thrombospondin 4 (THSB4) has not yet been associated with arthritis (Additional file 3), thrombospondin 1 (THBS1) is over-expressed in RA tissue [30].…”

Section: Resultsmentioning

confidence: 99%

RNA-seq analysis of synovial fibroblasts brings new insights into rheumatoid arthritis

et al. 2012

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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that primarily affects the joints and ultimately leads to their destruction. Growing evidence suggests that synvovial fibroblasts play important roles in the initiation and the perpetuation of RA but underlying molecular mechanisms are not understood fully. In the present study, Illumina RNA sequencing was used to profile two human normal control and two rheumatoid arthritis synvovial fibroblasts (RASFs) transcriptomes to gain insights into the roles of synvovial fibroblasts in RA.ResultsWe found that besides known inflammatory and immune responses, other novel dysregulated networks and pathways such as Cell Morphology, Cell-To-Cell Signaling and Interaction, Cellular Movement, Cellular Growth and Proliferation, and Cellular Development, may all contribute to the pathogenesis of RA. Our study identified several new genes and isoforms not previously associated with rheumatoid arthritis. 122 genes were up-regulated and 155 genes were down-regulated by at least two-fold in RASFs compared to controls. Of note, 343 known isoforms and 561 novel isoforms were up-regulated and 262 known isoforms and 520 novel isoforms were down-regulated by at least two-fold. The magnitude of difference and the number of differentially expressed known and novel gene isoforms were not detected previously by DNA microarray.ConclusionsSince the activation and proliferation of RASFs has been implicated in the pathogenesis of rheumatoid arthritis, further in-depth follow-up analysis of the transcriptional regulation reported in this study may shed light on molecular pathogenic mechanisms underlying synovial fibroblasts in arthritis and provide new leads of potential therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

RNA-seq analysis of synovial fibroblasts brings new insights into rheumatoid arthritis

et al. 2012

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“…Finally, it has been reported that, at least in vitro , α 2 -AR stimulation of type A (macrophage-like) and B (fibroblast-like) synoviocytes produced an increase and a decrease in the respective cell number, probably through Gi-coupled PLC activation and the resulting stimulation of the PKC betaII/MAP kinase (Mishima et al, 2001 ), providing preliminary evidence for a role of α 2 -AR regulating local innate immunity in synovial tissues.…”

Section: Adrenergic Modulation Of the Innate Immune Systemmentioning

confidence: 99%

Adrenergic regulation of innate immunity: a review

2015

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The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.

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“…The SNS regulates the functions of immune cells that mediate rheumatic disease through the activation of α- and β 2 -ARs expressed on their cell surfaces (10, 17–19). Sympathetic nerves target immune cells in secondary lymphoid organs (15, 16), and the immune cell infiltrates and tertiary lymph nodules that occur in the affected joints (20).…”

Section: Introductionmentioning

confidence: 99%

Targeting Î±- and Î²-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis

et al. 2014

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The sympathetic nervous system (SNS) regulates host defense responses and restores homeostasis. SNS-immune regulation is altered in rheumatoid arthritis (RA) and rodent models of RA, characterized by nerve remodeling in immune organs and defective adrenergic receptor (AR) signaling to immune cell targets. The SNS typically promotes or suppresses inflammation via α- and β2-AR activation, respectively, and indirectly drives humoral immunity by blocking Th1 cytokine secretion. Here, we investigate how β2-AR stimulation and/or α-AR blockade at disease onset affects disease pathology and cytokine profiles in relevant immune organs from male Lewis rats with adjuvant-induced arthritis (AA). Rats challenged to induce AA were treated with terbutaline (TERB), a β2-AR agonist (600 μg/kg/day) and/or phentolamine (PHEN), an α-AR antagonist (5.0 mg/kg/day) or vehicle from disease onset through severe disease. We report that in spleen, mesenteric (MLN) and draining lymph node (DLN) cells, TERB reduces proliferation, an effect independent of IL-2. TERB also fails to shift T helper (Th) cytokines from a Th1 to Th2 profile in spleen and MLN (no effect on IFN-γ) and DLN (greater IFN-γ) cells. In splenocytes, TERB, PHEN, and co-treatment (PT) promotes an anti-inflammatory profile (greater IL-10) and lowers TNF-α (PT only). In DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10. In MLN cells, TERB or PHEN lowers MLN cell secretion of TNF-α or IL-10, respectively. Collectively, our findings indicate disrupted β2-AR, but not α-AR signaling in AA. Aberrant β2-AR signaling consequently derails the sympathetic regulation of lymphocyte expansion, Th cell differentiation, and inflammation in the spleen, DLNs and MLs that is required for immune system homeostasis. Importantly, this study provides potential mechanisms through which reestablished balance between α- and β2-AR function in the immune system ameliorates inflammation and joint destruction in AA.

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Molecular Mechanisms for α2-Adrenoceptor-Mediated Regulation of Synoviocyte Populations

Cited by 19 publications

References 40 publications

RNA-seq analysis of synovial fibroblasts brings new insights into rheumatoid arthritis

RNA-seq analysis of synovial fibroblasts brings new insights into rheumatoid arthritis

Adrenergic regulation of innate immunity: a review

Targeting Î±- and Î²-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis

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