202-205
Clinicalrheumatology, 1992, 11, N ~ 2
Serum Levels of Interleukin-lb, Tumour Necrosis Factor-a and Interleukin-2 in Rheumatoid Arthritis. Correlation with Disease Activity L. A L T O M O N T E ,
A. Z O L I ,
L. M I R O N E ,
P. S C O L I E R I ,
M. M A G A R 0
Summary
Cytokines are potent immunoregulatory factors and may be directly involved in the disordered immunoregulation found in chronic rheumatic diseases. Interleukin-lb (IL-lb), Interleukin-2 (11.-2) and T u m o u r Necrosis Factor-a (TNF-a) have been implicated in the pathogenesis of rheumatoid arthritis (RA) as mediators of chronic inflammation. Serum levels of IL-lb and TNF-a measured by radioimmunoassay were significantly higher in patients with RA than in healthy controls of similar sex and age while serum levels of IL-2 were significantly lower in the same patients. Further IL-lb and TNF-a were significantly elevated in RA patients with active disease and IL-2 was significantly reduced when compared with patients with low active disease. Serum IL-lb and TNF-a appear to correlate with systemic inflammation, and systemic features of RA may result from dissemination of cytokines produced in the synovium. The role of IL-2 in RA remains controversial. Reduced levels of IL-2 may be an expression of a deficiency of T-cells to produce IL-2 in the active phases of RA or may be due to a possible absorption of IL-2 by lymphocyte receptors.
Key words: Rheumatoid Arthritis, Interleukin-lb, T u m o u r Necrosis Factor-a, Interleukin-2.
INTRODUCTION The role of biologically active soluble factors elaborated by monocytes and macrophages and by lymphocytes as important mediators of inflammation and joint destruction in rheumatoid arthritis (RA) is supported by numerous studies suggesting that cytokines may mediate cell-cell interactions that result in the release of tissuedamaging enzymes (1-4). Interleukin-lb (IL-lb), Interleukin-2 (IL-2) and Tumour Necrosis Factor-a (TNF-a) are among the many cytokines that can act, alone or in synergy, as mediators of tissue damage or chronic inflammation and which have been implicated in the pathogenesis of arthritis (5). IL-lb and TNF-a exhibit similar profiles of activities (6). IL-lb and TNF-a are able to act locally to induce bone and cartilage resorption (7,8). TNF-a is also able to accelerate proteoglycan degradation (9). Each can induce the production of the other and both cytokines, in-
Istituto di ClinicaMedica,Divisionedi Reumatologia,UniversitaCattolica del sacro Cuore, Roma, Italy.
dependently or together with interferon gamma, can induce the proliferation of synoviocytes (10). IL-lb and TNF-a may stimulate the production of prostaglandins and proteases with amplification of the destructive process in the joint (11,12). IL-2 is an activation, growth and differentiation factor produced exclusively by T-cells. IL-2 promotes growth and differentiation of T and B lymphocytes, enhances natural killer (NK) cell function and promotes activation of macrophages (2). Much of the information about cytokine action comes from in vitro studies and it is therefore difficult to draw conclusions about the in vivo effects. Several research groups (13-16) have measured the concentration of cytokines in serum and in synovial fluid. Bioassay methods provide valuable information about the many receptor-mediated activities of cytokines, but the results are variable, probably because of the ubiquitous presence of inhibitors in these fluids, and the impracticability of using a large number of samples. Immunoassay methods, recently introduced, give less variable results and are very useful for study of cytokine concentrations in biological fluid of a large number of patients.
IL-lb, IL-2 and TNF-a in rheumatoid arthritis
Table I :
Baseline characteristic of patients in group A and B
Age in years (range) Disease duration in years (range) ESR (mm 1st hour) Swollen joints (number) Tender joints (number) Morning stiffness (minutes)
Group A
Group B
18-48 0.5-4 >30 ~3 ~-6 .~30
20-52 0.3-3.5
Clinicalrheumatology, 1992, 11, N ~ 2
Serum Levels of Interleukin-lb, Tumour Necrosis Factor-a and Interleukin-2 in Rheumatoid Arthritis. Correlation with Disease Activity L. A L T O M O N T E ,
A. Z O L I ,
L. M I R O N E ,
P. S C O L I E R I ,
M. M A G A R 0
Summary
Cytokines are potent immunoregulatory factors and may be directly involved in the disordered immunoregulation found in chronic rheumatic diseases. Interleukin-lb (IL-lb), Interleukin-2 (11.-2) and T u m o u r Necrosis Factor-a (TNF-a) have been implicated in the pathogenesis of rheumatoid arthritis (RA) as mediators of chronic inflammation. Serum levels of IL-lb and TNF-a measured by radioimmunoassay were significantly higher in patients with RA than in healthy controls of similar sex and age while serum levels of IL-2 were significantly lower in the same patients. Further IL-lb and TNF-a were significantly elevated in RA patients with active disease and IL-2 was significantly reduced when compared with patients with low active disease. Serum IL-lb and TNF-a appear to correlate with systemic inflammation, and systemic features of RA may result from dissemination of cytokines produced in the synovium. The role of IL-2 in RA remains controversial. Reduced levels of IL-2 may be an expression of a deficiency of T-cells to produce IL-2 in the active phases of RA or may be due to a possible absorption of IL-2 by lymphocyte receptors.
Key words: Rheumatoid Arthritis, Interleukin-lb, T u m o u r Necrosis Factor-a, Interleukin-2.
INTRODUCTION The role of biologically active soluble factors elaborated by monocytes and macrophages and by lymphocytes as important mediators of inflammation and joint destruction in rheumatoid arthritis (RA) is supported by numerous studies suggesting that cytokines may mediate cell-cell interactions that result in the release of tissuedamaging enzymes (1-4). Interleukin-lb (IL-lb), Interleukin-2 (IL-2) and Tumour Necrosis Factor-a (TNF-a) are among the many cytokines that can act, alone or in synergy, as mediators of tissue damage or chronic inflammation and which have been implicated in the pathogenesis of arthritis (5). IL-lb and TNF-a exhibit similar profiles of activities (6). IL-lb and TNF-a are able to act locally to induce bone and cartilage resorption (7,8). TNF-a is also able to accelerate proteoglycan degradation (9). Each can induce the production of the other and both cytokines, in-
Istituto di ClinicaMedica,Divisionedi Reumatologia,UniversitaCattolica del sacro Cuore, Roma, Italy.
dependently or together with interferon gamma, can induce the proliferation of synoviocytes (10). IL-lb and TNF-a may stimulate the production of prostaglandins and proteases with amplification of the destructive process in the joint (11,12). IL-2 is an activation, growth and differentiation factor produced exclusively by T-cells. IL-2 promotes growth and differentiation of T and B lymphocytes, enhances natural killer (NK) cell function and promotes activation of macrophages (2). Much of the information about cytokine action comes from in vitro studies and it is therefore difficult to draw conclusions about the in vivo effects. Several research groups (13-16) have measured the concentration of cytokines in serum and in synovial fluid. Bioassay methods provide valuable information about the many receptor-mediated activities of cytokines, but the results are variable, probably because of the ubiquitous presence of inhibitors in these fluids, and the impracticability of using a large number of samples. Immunoassay methods, recently introduced, give less variable results and are very useful for study of cytokine concentrations in biological fluid of a large number of patients.
IL-lb, IL-2 and TNF-a in rheumatoid arthritis
Table I :
Baseline characteristic of patients in group A and B
Age in years (range) Disease duration in years (range) ESR (mm 1st hour) Swollen joints (number) Tender joints (number) Morning stiffness (minutes)
Group A
Group B
18-48 0.5-4 >30 ~3 ~-6 .~30
20-52 0.3-3.5
