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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

Ex vivo proliferation and IL-2 production by spleen (SPL) cells 72 and 24 h post-culture, respectively. 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)3H-Thymidine incorporation into spleen cells was significantly lower in all drug-treated groups compared with VEH controls. The horizontal light gray bar represents the range of non-specific background in untreated non-arthritic rats. N = 8. ***p < 0.001. (B) IL-2 secreted by spleen cells was greater with PHEN compared with VEH treatment, but IL-2 concentrations in the other treatments did not differ from VEH-treated rats. N = 8. *p < 0.05.
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Figure 4: Ex vivo proliferation and IL-2 production by spleen (SPL) cells 72 and 24 h post-culture, respectively. 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)3H-Thymidine incorporation into spleen cells was significantly lower in all drug-treated groups compared with VEH controls. The horizontal light gray bar represents the range of non-specific background in untreated non-arthritic rats. N = 8. ***p < 0.001. (B) IL-2 secreted by spleen cells was greater with PHEN compared with VEH treatment, but IL-2 concentrations in the other treatments did not differ from VEH-treated rats. N = 8. *p < 0.05.

Mentions: Thymidine incorporation was greater in the spleen cells from VEH-treated arthritic than untreated non-arthritic rats (light gray horizontal bar; Figure 4A). Splenocyte proliferation was 28-fold greater than PBMC proliferation (Figure 2A). In vivo treatment with TERB, PHEN, or PT markedly reduced spleen cell proliferation compared with VEH treatment (Figure 4A; p < 0.001). IL-2 levels were low (28 ± 5 pg/ml), but detectable in the VEH-treated arthritic animals (Figure 4B). Despite the drug-induced suppression in proliferation (Figure 4A), IL-2 concentrations (Figure 4B) were no different in cultures from TERB- or PT-treated rats, and elevated in cultures from PHEN-treated rats compared with VEH treatment (p < 0.05).


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)

Ex vivo proliferation and IL-2 production by spleen (SPL) cells 72 and 24 h post-culture, respectively. 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)3H-Thymidine incorporation into spleen cells was significantly lower in all drug-treated groups compared with VEH controls. The horizontal light gray bar represents the range of non-specific background in untreated non-arthritic rats. N = 8. ***p < 0.001. (B) IL-2 secreted by spleen cells was greater with PHEN compared with VEH treatment, but IL-2 concentrations in the other treatments did not differ from VEH-treated rats. N = 8. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Ex vivo proliferation and IL-2 production by spleen (SPL) cells 72 and 24 h post-culture, respectively. 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)3H-Thymidine incorporation into spleen cells was significantly lower in all drug-treated groups compared with VEH controls. The horizontal light gray bar represents the range of non-specific background in untreated non-arthritic rats. N = 8. ***p < 0.001. (B) IL-2 secreted by spleen cells was greater with PHEN compared with VEH treatment, but IL-2 concentrations in the other treatments did not differ from VEH-treated rats. N = 8. *p < 0.05.
Mentions: Thymidine incorporation was greater in the spleen cells from VEH-treated arthritic than untreated non-arthritic rats (light gray horizontal bar; Figure 4A). Splenocyte proliferation was 28-fold greater than PBMC proliferation (Figure 2A). In vivo treatment with TERB, PHEN, or PT markedly reduced spleen cell proliferation compared with VEH treatment (Figure 4A; p < 0.001). IL-2 levels were low (28 ± 5 pg/ml), but detectable in the VEH-treated arthritic animals (Figure 4B). Despite the drug-induced suppression in proliferation (Figure 4A), IL-2 concentrations (Figure 4B) were no different in cultures from TERB- or PT-treated rats, and elevated in cultures from PHEN-treated rats compared with VEH treatment (p < 0.05).

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