Effects of aging and cytokine blockade on inflammatory cachexia 

B. Fathalla^1,2, K. Hamada¹, E. Vannier^1,2, D. Smith¹, C. Edwards III³, R. Roubenoff^1,2

¹Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts; ²Tufts-New England Medical Center, Boston, Massachusetts; ³Amgen, Inc., Thousand Oaks, California, USA.

ABSTRACT
Objective
To evaluate the role of aging and specific cytokine blockade in the etiology of cachexia caused by adjuvant arthritis (AA), a model of cytokine-associated cachexia. 

Methods
AA was induced in Lewis rats using CFA. In Experiment 1, severity of AA and inflammatory cachexia was assessed in young (Y, age 2-6 months, n = 132) and old rats (O, age 18-22 months, n = 40). In Experiment 2, young rats were divided into 5 different intervention groups: Saline-injected (n = 66); CFA-injected (n = 78); CFA-injected and treated with IL-1 receptor antagonist (IL-1Ra, n = 18); CFA-injected and treated with soluble TNF receptor type I (sTNFrI, n = 27); and CFA-injected and treated with both IL-1Ra and sTNFrI (both treatments, n = 8).

Results
In Experiment 1, young Lewis rats developed more severe arthritis (mean joint score on day 21 = 5.1 ± 0.3) compared to the old group (0.6 ± 0.6, p < 0.0001). The young group with AA lost 2.1% of baseline total body weight loss compared to 13.8% total body weight gain in controls (p < 0.0001). In contrast, old rats injected with CFA lost as much weight (-11%) as age-matched saline injected controls (-13%, p > 0.05, n = 18, age 18-22 months). In Experiment 2, mean joint scores in rats treated with IL-1Ra, sTNFrI or both were higher then untreated rats injected with CFA (p < 0.0001). Despite this, rats given both IL-1Ra and sTNFrI lost less weight on day 16 (p < 0.01) and 21 (p < 0.002) than untreated rats or those rats treated with either IL-1Ra or sTNFrI.

Conclusion
Lewis rats aged 2-6 months are more susceptible to developing AA than older rats (age range 18-22 months). Inhibition of both IL-1 and TNF is needed to mitigate AA-associated weight loss, and this effect is dissociated from the effect of such inhibition on joint inflammation.

Key words
Adjuvant arthritis, inflammatory cachexia, IL-1 and TNF.

Supported by a Clinical Science Grant from the Arthritis Foundation, NIH Grants AG15797 and M01-RR00054, USDA Cooperative Agreement 58-1950-9-001, and a grant from Amgen, Inc. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Please address correspondence to: Ronenn Roubenoff, MD, MHS, NEPS Laboratory, JM USDA HNRCA, Tufts University, 711 Washington Street, Boston, MA 02111, USA. 
E-mail: Roubenoff@mpi.com 

Clin Exp Rheumatol 2004; 22: 85-90.
© Copyright Clinical and Experimental Rheumatology 2004.

Abbreviations:
AA: Adjuvant arthritis.
CFA: Complete Freund's adjuvant.
IL-1Ra: Interleukin-1 receptor antag- onist.
PEGsTNFrI: PEGylated TNF receptor p55.
sTNFrI: Soluble TNF receptor p55.
TNF: Tumor Necrosis Factor.