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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

Cytokine production by draining lymph node (DLN) cells after 24 h of culture. 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) IL-4 production was augmented by treatment with PT over that found in VEH controls. N = 8. *p < 0.05. (B) IFN-γ concentrations were higher in TERB- and PT- than with VEH-treated rats. N = 8. *p < 0.05; **p < 0.01. (C) TNF-α levels were similar in all groups. N = 8. p < 0.05. (D) IL-10 secretion was elevated in rats treated with PT over that seen with VEH treatment. N = 8. *p < 0.05.
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Figure 7: Cytokine production by draining lymph node (DLN) cells after 24 h of culture. 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) IL-4 production was augmented by treatment with PT over that found in VEH controls. N = 8. *p < 0.05. (B) IFN-γ concentrations were higher in TERB- and PT- than with VEH-treated rats. N = 8. *p < 0.05; **p < 0.01. (C) TNF-α levels were similar in all groups. N = 8. p < 0.05. (D) IL-10 secretion was elevated in rats treated with PT over that seen with VEH treatment. N = 8. *p < 0.05.

Mentions: In vivo administration of PT significantly increased IL-4 levels over levels in VEH-treated arthritic rats (Figure 7A; p < 0.05), but there was no effect of TERB or PHEN treatment on IL-4 concentrations. Interestingly, TERB and PT, but not PHEN, increased IFN-γ production in DLN cells compared with VEH treatment (pTERB < 0.05; pPT < 0.01) (Figure 7B). In contrast, none of the adrenergic treatments altered TNF-α production in DLN cells compared with VEH-treated arthritic rats (Figure 7C). PT treatment significantly increased the IL-10 concentration compared with VEH-treated arthritic rats (pPT < 0.05) (Figure 7D), but treatment with TERB or PHEN had no effect compared with VEH-treated arthritic rats.


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)

Cytokine production by draining lymph node (DLN) cells after 24 h of culture. 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) IL-4 production was augmented by treatment with PT over that found in VEH controls. N = 8. *p < 0.05. (B) IFN-γ concentrations were higher in TERB- and PT- than with VEH-treated rats. N = 8. *p < 0.05; **p < 0.01. (C) TNF-α levels were similar in all groups. N = 8. p < 0.05. (D) IL-10 secretion was elevated in rats treated with PT over that seen with VEH treatment. N = 8. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Cytokine production by draining lymph node (DLN) cells after 24 h of culture. 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) IL-4 production was augmented by treatment with PT over that found in VEH controls. N = 8. *p < 0.05. (B) IFN-γ concentrations were higher in TERB- and PT- than with VEH-treated rats. N = 8. *p < 0.05; **p < 0.01. (C) TNF-α levels were similar in all groups. N = 8. p < 0.05. (D) IL-10 secretion was elevated in rats treated with PT over that seen with VEH treatment. N = 8. *p < 0.05.
Mentions: In vivo administration of PT significantly increased IL-4 levels over levels in VEH-treated arthritic rats (Figure 7A; p < 0.05), but there was no effect of TERB or PHEN treatment on IL-4 concentrations. Interestingly, TERB and PT, but not PHEN, increased IFN-γ production in DLN cells compared with VEH treatment (pTERB < 0.05; pPT < 0.01) (Figure 7B). In contrast, none of the adrenergic treatments altered TNF-α production in DLN cells compared with VEH-treated arthritic rats (Figure 7C). PT treatment significantly increased the IL-10 concentration compared with VEH-treated arthritic rats (pPT < 0.05) (Figure 7D), but treatment with TERB or PHEN had no effect compared with VEH-treated arthritic rats.

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