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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

Indices of disease severity. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT) initiated 12 days after adjuvant challenge. (A) Mean Footpad widths ± SEM were significantly reduced in TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) treated compared with VEH (black bar) treated rats. Light gray horizontal bar represents the mean footpad width ± SEM of naïve rat. N = 8. ***p < 0.001. (B) Mean radiographic scores ± SEM for, AA rats treated with TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) were decreased compared with VEH (black bar). N = 8. *p < 0.05; **p < 0.01. (C) Stack-plots showing the contribution of each radiographic score component to the mean total radiographic score for rats treated with VEH, TERB, PHEN, or PT. Swelling, blue; joint narrowing (JT NR), red; osteoporosis, green; bone loss, purple; periosteal bone formation (POBF), turquoise. (D) Radiograph of the hind limb representative of normal untreated rats. (E) Radiograph of the hind limb representative of vehicle (VEH)-treated rats. (F) Radiograph of the hind limb representative TERB-treated rats. (G) Radiograph of the hind limb representative of PHEN-treated rats. (H) Radiograph of the hind limb representative of PT-treated rats. (I) Mean body weights in grams (g) ±SEM for rats treated with vehicle (VEH), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT). The light gray bar represents the range of body weights for untreated non-arthritic rats. N = 8. **p < 0.01. (J) Mean spleen weights in grams (g) ±SEM for rats challenged with adjuvant and treated with vehicle (VEH) or phentolamine and terbutaline (PT). The light gray bar represents the range for normal spleen weights of untreated non-arthritic rats. N = 8. *p < 0.05.
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Figure 1: Indices of disease severity. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT) initiated 12 days after adjuvant challenge. (A) Mean Footpad widths ± SEM were significantly reduced in TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) treated compared with VEH (black bar) treated rats. Light gray horizontal bar represents the mean footpad width ± SEM of naïve rat. N = 8. ***p < 0.001. (B) Mean radiographic scores ± SEM for, AA rats treated with TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) were decreased compared with VEH (black bar). N = 8. *p < 0.05; **p < 0.01. (C) Stack-plots showing the contribution of each radiographic score component to the mean total radiographic score for rats treated with VEH, TERB, PHEN, or PT. Swelling, blue; joint narrowing (JT NR), red; osteoporosis, green; bone loss, purple; periosteal bone formation (POBF), turquoise. (D) Radiograph of the hind limb representative of normal untreated rats. (E) Radiograph of the hind limb representative of vehicle (VEH)-treated rats. (F) Radiograph of the hind limb representative TERB-treated rats. (G) Radiograph of the hind limb representative of PHEN-treated rats. (H) Radiograph of the hind limb representative of PT-treated rats. (I) Mean body weights in grams (g) ±SEM for rats treated with vehicle (VEH), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT). The light gray bar represents the range of body weights for untreated non-arthritic rats. N = 8. **p < 0.01. (J) Mean spleen weights in grams (g) ±SEM for rats challenged with adjuvant and treated with vehicle (VEH) or phentolamine and terbutaline (PT). The light gray bar represents the range for normal spleen weights of untreated non-arthritic rats. N = 8. *p < 0.05.

Mentions: Footpad widths and X-ray scores from drug- and VEH-treated rats are presented in Figures 1A,B, respectively. All adrenergic interventions significantly reduced the dorsoplantar footpad width compared with VEH-treated arthritic rats (p < 0.001) (Figure 1A). All arthritic rats had greater footpad widths compared with non-AA rats (normal range indicated by the gray horizontal bar shown in Figure 1A). There was also a dramatic reduction in the radiographic scores from the arthritic rats treated with TERB compared with VEH-treated arthritic rats (Figure 1B; pTERB < 0.05, pPHEN < 0.05, or pPT < 0.01). X-rays of ankle joints from VEH-treated arthritic rats showed greater soft tissue swelling and joint destruction compared with arthritic rats treated with TERB, PHEN, or PT (Figures 1D–H). These observations were confirmed with X-ray analysis (Figure 1C). Figure 1C demonstrates the adrenergic drug-induced reduction in the components that comprise the radiographic scores. Adrenergic drug treatments reduced periosteal bone formation (POBF) 260–490%, bone erosions 170–270%, osteoporosis 190–320%, cartilage loss (JT NR) 140–220%, and soft tissue swelling 140–290% compared with VEH-treated arthritic animals. The rank order of potency for reducing soft tissue swelling and lower X-ray scores for the treatments was PT > TERB = PHEN > VEH.


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)

Indices of disease severity. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT) initiated 12 days after adjuvant challenge. (A) Mean Footpad widths ± SEM were significantly reduced in TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) treated compared with VEH (black bar) treated rats. Light gray horizontal bar represents the mean footpad width ± SEM of naïve rat. N = 8. ***p < 0.001. (B) Mean radiographic scores ± SEM for, AA rats treated with TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) were decreased compared with VEH (black bar). N = 8. *p < 0.05; **p < 0.01. (C) Stack-plots showing the contribution of each radiographic score component to the mean total radiographic score for rats treated with VEH, TERB, PHEN, or PT. Swelling, blue; joint narrowing (JT NR), red; osteoporosis, green; bone loss, purple; periosteal bone formation (POBF), turquoise. (D) Radiograph of the hind limb representative of normal untreated rats. (E) Radiograph of the hind limb representative of vehicle (VEH)-treated rats. (F) Radiograph of the hind limb representative TERB-treated rats. (G) Radiograph of the hind limb representative of PHEN-treated rats. (H) Radiograph of the hind limb representative of PT-treated rats. (I) Mean body weights in grams (g) ±SEM for rats treated with vehicle (VEH), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT). The light gray bar represents the range of body weights for untreated non-arthritic rats. N = 8. **p < 0.01. (J) Mean spleen weights in grams (g) ±SEM for rats challenged with adjuvant and treated with vehicle (VEH) or phentolamine and terbutaline (PT). The light gray bar represents the range for normal spleen weights of untreated non-arthritic rats. N = 8. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 1: Indices of disease severity. Animals were treated with twice-daily i.p. injections of vehicle (VEH, black bars), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT) initiated 12 days after adjuvant challenge. (A) Mean Footpad widths ± SEM were significantly reduced in TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) treated compared with VEH (black bar) treated rats. Light gray horizontal bar represents the mean footpad width ± SEM of naïve rat. N = 8. ***p < 0.001. (B) Mean radiographic scores ± SEM for, AA rats treated with TERB (white bar), PHEN (dark gray bar), and PT (light gray bar) were decreased compared with VEH (black bar). N = 8. *p < 0.05; **p < 0.01. (C) Stack-plots showing the contribution of each radiographic score component to the mean total radiographic score for rats treated with VEH, TERB, PHEN, or PT. Swelling, blue; joint narrowing (JT NR), red; osteoporosis, green; bone loss, purple; periosteal bone formation (POBF), turquoise. (D) Radiograph of the hind limb representative of normal untreated rats. (E) Radiograph of the hind limb representative of vehicle (VEH)-treated rats. (F) Radiograph of the hind limb representative TERB-treated rats. (G) Radiograph of the hind limb representative of PHEN-treated rats. (H) Radiograph of the hind limb representative of PT-treated rats. (I) Mean body weights in grams (g) ±SEM for rats treated with vehicle (VEH), terbutaline (TERB), phentolamine (PHEN), or phentolamine and terbutaline (PT). The light gray bar represents the range of body weights for untreated non-arthritic rats. N = 8. **p < 0.01. (J) Mean spleen weights in grams (g) ±SEM for rats challenged with adjuvant and treated with vehicle (VEH) or phentolamine and terbutaline (PT). The light gray bar represents the range for normal spleen weights of untreated non-arthritic rats. N = 8. *p < 0.05.
Mentions: Footpad widths and X-ray scores from drug- and VEH-treated rats are presented in Figures 1A,B, respectively. All adrenergic interventions significantly reduced the dorsoplantar footpad width compared with VEH-treated arthritic rats (p < 0.001) (Figure 1A). All arthritic rats had greater footpad widths compared with non-AA rats (normal range indicated by the gray horizontal bar shown in Figure 1A). There was also a dramatic reduction in the radiographic scores from the arthritic rats treated with TERB compared with VEH-treated arthritic rats (Figure 1B; pTERB < 0.05, pPHEN < 0.05, or pPT < 0.01). X-rays of ankle joints from VEH-treated arthritic rats showed greater soft tissue swelling and joint destruction compared with arthritic rats treated with TERB, PHEN, or PT (Figures 1D–H). These observations were confirmed with X-ray analysis (Figure 1C). Figure 1C demonstrates the adrenergic drug-induced reduction in the components that comprise the radiographic scores. Adrenergic drug treatments reduced periosteal bone formation (POBF) 260–490%, bone erosions 170–270%, osteoporosis 190–320%, cartilage loss (JT NR) 140–220%, and soft tissue swelling 140–290% compared with VEH-treated arthritic animals. The rank order of potency for reducing soft tissue swelling and lower X-ray scores for the treatments was PT > TERB = PHEN > VEH.

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