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Targeting α- and β-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis.

Lubahn CL, Lorton D, Schaller JA, Sweeney SJ, Bellinger DL - Front Immunol (2014)

Bottom Line: 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 DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10.

View Article: PubMed Central - PubMed

Affiliation: College of Arts and Sciences, Kent State University , Kent, OH , USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Proliferation of mesenteric lymph node (MLN) cells and IL-2 production. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB, white bars), phentolamine (PHEN, dark gray bars), or phentolamine and terbutaline (PT, light gray bars) initiated 12 days after adjuvant challenge. (A) All drug treatments suppressed proliferation of MLN cells compared with VEH treatment. Horizontal light gray bar demonstrates non-specific background. (B) IL-2 production did not differ between treatment groups. N = 8. ***p < 0.001.
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Figure 8: Proliferation of mesenteric lymph node (MLN) cells and IL-2 production. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB, white bars), phentolamine (PHEN, dark gray bars), or phentolamine and terbutaline (PT, light gray bars) initiated 12 days after adjuvant challenge. (A) All drug treatments suppressed proliferation of MLN cells compared with VEH treatment. Horizontal light gray bar demonstrates non-specific background. (B) IL-2 production did not differ between treatment groups. N = 8. ***p < 0.001.

Mentions: Proliferative responses of DLN cells from VEH-treated arthritic animals were elevated compared with DLN cells from non-arthritic rats (light gray horizontal bars; Figure 6A). Additionally, DLN cell proliferation in VEH-treated rats was reduced 1.5-fold compared with the spleen (Figure 4A), but 19- or 6.7-fold higher than for PBMCs (Figure 2A) or MLN cells (Figure 8A), respectively. In vivo treatment with TERB, PHEN, or PT dramatically (>600%) reduced DLN cell proliferation compared with the VEH-treated arthritic animals (Figure 6A; p < 0.001). In VEH-treated arthritic rats, IL-2 concentrations from DLN cell cultures were similar to spleen cell cultures (Figure 6B), and much lower than PBMC cell cultures (Figure 4B). Treatment with TERB or PHEN tended to increase IL-2 concentrations (p < 0.1; Figure 6B), but PT treatment significantly elevated IL-2 production compared with DLN cells from VEH-treated arthritic rats (p < 0.05) (Figure 6B).


Targeting α- and β-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis.

Lubahn CL, Lorton D, Schaller JA, Sweeney SJ, Bellinger DL - Front Immunol (2014)

Proliferation of mesenteric lymph node (MLN) cells and IL-2 production. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB, white bars), phentolamine (PHEN, dark gray bars), or phentolamine and terbutaline (PT, light gray bars) initiated 12 days after adjuvant challenge. (A) All drug treatments suppressed proliferation of MLN cells compared with VEH treatment. Horizontal light gray bar demonstrates non-specific background. (B) IL-2 production did not differ between treatment groups. N = 8. ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127464&req=5

Figure 8: Proliferation of mesenteric lymph node (MLN) cells and IL-2 production. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB, white bars), phentolamine (PHEN, dark gray bars), or phentolamine and terbutaline (PT, light gray bars) initiated 12 days after adjuvant challenge. (A) All drug treatments suppressed proliferation of MLN cells compared with VEH treatment. Horizontal light gray bar demonstrates non-specific background. (B) IL-2 production did not differ between treatment groups. N = 8. ***p < 0.001.
Mentions: Proliferative responses of DLN cells from VEH-treated arthritic animals were elevated compared with DLN cells from non-arthritic rats (light gray horizontal bars; Figure 6A). Additionally, DLN cell proliferation in VEH-treated rats was reduced 1.5-fold compared with the spleen (Figure 4A), but 19- or 6.7-fold higher than for PBMCs (Figure 2A) or MLN cells (Figure 8A), respectively. In vivo treatment with TERB, PHEN, or PT dramatically (>600%) reduced DLN cell proliferation compared with the VEH-treated arthritic animals (Figure 6A; p < 0.001). In VEH-treated arthritic rats, IL-2 concentrations from DLN cell cultures were similar to spleen cell cultures (Figure 6B), and much lower than PBMC cell cultures (Figure 4B). Treatment with TERB or PHEN tended to increase IL-2 concentrations (p < 0.1; Figure 6B), but PT treatment significantly elevated IL-2 production compared with DLN cells from VEH-treated arthritic rats (p < 0.05) (Figure 6B).

Bottom Line: 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 DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10.

View Article: PubMed Central - PubMed

Affiliation: College of Arts and Sciences, Kent State University , Kent, OH , USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus