Introduction

Cure Arthritis Naturally

Beat Arthritis Naturally

Get Instant Access

It is now well recognized that the spontaneous production of pro-inflammatory cytokines, in particular TNF, IL-1 and IL-6, produced locally in the inflamed synovial joint contribute directly to the pathogenesis of rheumatoid arthritis (RA) [1]. These observations have arisen initially from ex vivo studies with human synovial cultures, immunohistochemical and mRNA analysis of synovium and in vivo studies in animal models of arthritis. Blocking TNF ameliorated collagen type II arthritis, even after disease onset, and transgenic mice, overexpressing TNF, develop an erosive polyarthritis; these investigations have led to the development of several TNF and IL-1 inhibitors. Currently licensed are Infliximab Remicade (chimeric anti-TNF antibody) and etanercept (TNF receptor fusion protein) (adalimumab, humira human anti-TNF, anakinra (Kineret) and IL-1 receptor antagonists.

Therapies targeting TNF are useful in multiple chronic inflammatory disease including JRA, Crohn's disease, psoriasis, psoriatic arthritis and ankylosing spondylitis [2], it is also apparent that long-term blockade of a cytokine such as TNF, which is important in innate and acquired immunity, may lead to an increase in latent and/or opportunistic infections. This is now apparent, with a small but significant increase in unusual infections, as well as the re-emergence of latent TB in endemic areas, particularly in Central and Eastern Europe in about 1/2,000 anti-TNF patients [3].

It is thus important in the absence of screening or prophylaxis to understand what mechanisms lead to the production of pro-inflammatory cytokines in RA synovial tissue, and whether the molecular mechanisms differ from those generating TNF in host defence situation.

It has been observed that whilst the production of multiple pro-inflammatory cytokines and enzymes is highly increased in RA (Table 1), this activity is offset to some degree by the action of several endogenous anti-inflammatory cytokines and cytokine inhibitors. Of particular importance in this respect is IL-10, an important regulator of TNFa and IL-10, spontaneously produced by macrophages and other cells in the rheumatoid joint [4, 5]. Thus if endogenous IL-10 is blocked in RA synovial cell cultures, the spontaneous production of both TNF and IL-1 increased 2-fold [4]. Thus there is an important need to develop therapies that block the pro-inflammatory pathways in synovium, but leave unaffected those that regulate immunoregulatory cytokines such as IL-10, and if possible leave the capacity to make TNF in infection.

Table 1 Cytokines and chemokines expressed in synovial tissue (modified and updated from [1])

Cytokine

mRNA

Protein

References

IL-1 a and ß

(interleukin 1)

Yes

Yes

5,53-60

IL-2

(interleukin 2)

Yes

+/-

61,62

IL-3

(interleukin 3)

?

?

62

IL-6

(interleukin 6)

Yes

Yes

56,63-68

IL-7

(interleukin 7)

Yes

Yes

68

IL-11

(interleukin 11)

Yes

Yes

63,69

IL-12

(interleukin 12)

Yes

Yes

70

IL-15

(interleukin 15)

Yes

Yes

19

IL-17

(interleukin 17)

Yes

Yes

71

IL-18

(interleukin 18)

Yes

Yes

72

TNFa

(tumour necrosis factor)

Yes

Yes

55-58, 73-76

LT

(lymphotoxin)

Yes

+/-

74, 77

GM-CSF

(granulocyte macrophage colony-stimulating factor)

Yes

Yes

78-80

M-CSF

(macrophage colony-stimulating factor)

Yes

Yes

62

LIF

(leukocyte inhibitory factor)

Yes

Yes

63

Onco M

(oncostatin M)

Yes

Yes

63

IFNa

(interferon alpha)

Yes

Yes

75

IFNß

(interferon beta)

?

?

IFNy

(interferon gamma)

Yes

+/-

56, 61, 77

IL-4

(interleukin 4)

?

No

81

IL-10

(interleukin 10)

Yes

Yes

4, 82-84

IL-13

(interleukin 13)

Yes

Yes

85

IL-16

(interleukin 16)

Yes

Yes

86, 87

TGFß

(transforming growth factor beta)

Yes

Yes

81,88-93

IL-8

(interleukin 8/CXCL8)

Yes

Yes

94-98

Groa

(melanoma growth stimulating activity/CXCL1)

Yes

Yes

97

MIP-1a

(macrophage inflammatory protein 1alpha/CCL3)

Yes

Yes

97, 99

MIP-1ß

(macrophage inflammatory protein 1 beta/CCL4)

Yes

Yes

97

MCP-1

(monocyte chemoattractant protein 1/CCL2)

Yes

Yes

95,97,100-102

Table 1 (continued)

Cytokine

mRNA

Protein

References

ENA-78

(epithelial neutrophil activating peptide 78/CXCL5)

Yes

Yes

103

RANTES

(regulated upon activation t cell expressed & secreted/CCL5)

Yes

Yes

104

DC-CK1

(dendritic-cell-derived CC chemokine-1/CCL18)

Yes

?

105

MIP-3a

(macrophage inflammatory protein-3 alpha/CCL20)

?

?

106,107

SDF-1a/ß

(Stromal-cell-derived factor-1 alpha/beta/CXCL12)

?

Yes

108

MIG

(monokine induced by interferony/CXCL9)

Yes

?

109,110

IP-10

(Interferon-inducible protein-10/CXCL10)

Yes

?

109

Fractalkine

(CX3CL1)

?

Yes

111

BCA-1

(B-cell-attracting chemokine-1/CXCL13)

Yes

Yes

112

VEGF

(vascular endothelial cell growth factor)

Yes

Yes

113, 114

FGF

(fibroblast growth factor)

Yes

Yes

89,115-118

PDGF

(platelet-derived growth factor)

Yes

Yes

118-120

Was this article helpful?

0 0
Arthritis Relief and Prevention

Arthritis Relief and Prevention

This report may be oh so welcome especially if theres no doctor in the house Take Charge of Your Arthritis Now in less than 5-Minutes the time it takes to make an appointment with your healthcare provider Could you use some help understanding arthritis Maybe a little gentle, bedside manner in your battle for joint pain relief would be great Well, even if you are not sure if arthritis is the issue with you or your friend or loved one.

Get My Free Ebook


Post a comment