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The biological and clinical importance of the 'new generation' cytokines in rheumatic diseases.

Gabay C, McInnes IB - Arthritis Res. Ther. (2009)

Bottom Line: A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6.In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17.Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, University Hospitals of Geneva & Department of Pathology-Immunology, University of Geneva Medical School, 1211 Geneva 14, Switzerland. cem.gabay@hcuge.ch

ABSTRACT
A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6. The introduction of these therapies should be considered a breakthrough in the management of several rheumatic diseases. However, many patients will exhibit no or only partial response to these therapies, thus emphasising the importance of exploring other therapeutic strategies. In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17. Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases. Targeting of some of these cytokines has already been tested in clinical trials with interesting results.

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IL-1RAcP is the common co-receptor. Several members of the IL-1 family of cytokines, including IL-1 (IL-1F1 and IL-1F2), IL-1F6, IL-1F8, IL-1F9, and IL-33 (IL-1F11), bind to their specific cell surface receptors, including IL-1RI, IL-1Rrp2, and T1/ST2, but use IL-1RAcP as a common co-receptor. All of these cytokines stimulate common intracellular signalling events. IL-1RAcP is ubiquitously expressed, whereas the other IL-1 receptors are more selectively expressed in different cell types. Two receptor antagonists, IL-1Ra and IL-1F5, inhibit the biologic activities of the ligands IL-1 and IL-1F6, IL-1F8, and IL-1F9, respectively. In addition, soluble IL-1RAcP inhibits the effect of IL-1 and IL-33 when present in combination with their specific soluble receptors, including IL-1RII and sST2. ERK 1/2, extracellular-regulated kinase 1/2; IL, interleukin; IRAK, interleukin-1 receptor-associated kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation 88; NF-κB, nuclear factor-kappa-B; TRAF6, tumour necrosis factor receptor-associated factor 6.
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Figure 1: IL-1RAcP is the common co-receptor. Several members of the IL-1 family of cytokines, including IL-1 (IL-1F1 and IL-1F2), IL-1F6, IL-1F8, IL-1F9, and IL-33 (IL-1F11), bind to their specific cell surface receptors, including IL-1RI, IL-1Rrp2, and T1/ST2, but use IL-1RAcP as a common co-receptor. All of these cytokines stimulate common intracellular signalling events. IL-1RAcP is ubiquitously expressed, whereas the other IL-1 receptors are more selectively expressed in different cell types. Two receptor antagonists, IL-1Ra and IL-1F5, inhibit the biologic activities of the ligands IL-1 and IL-1F6, IL-1F8, and IL-1F9, respectively. In addition, soluble IL-1RAcP inhibits the effect of IL-1 and IL-33 when present in combination with their specific soluble receptors, including IL-1RII and sST2. ERK 1/2, extracellular-regulated kinase 1/2; IL, interleukin; IRAK, interleukin-1 receptor-associated kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation 88; NF-κB, nuclear factor-kappa-B; TRAF6, tumour necrosis factor receptor-associated factor 6.

Mentions: IL-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 family receptor T1/ST2. IL-33 is produced as a 30-kDa propeptide [12]. The biologic effects of IL-33 are mediated upon binding to T1/ST2 and the recruitment of IL-1RAcP, the common co-receptor of IL-1α, IL-1β, IL-1F6, IL-1F8, and IL-1F9 (Figure 1). Cell signals induced by IL-33 are similar to those of IL-1 and include ERK, mitogen-activated protein kinase (MAPK) p38 and JNK, and NF-κB activation [13].


The biological and clinical importance of the 'new generation' cytokines in rheumatic diseases.

Gabay C, McInnes IB - Arthritis Res. Ther. (2009)

IL-1RAcP is the common co-receptor. Several members of the IL-1 family of cytokines, including IL-1 (IL-1F1 and IL-1F2), IL-1F6, IL-1F8, IL-1F9, and IL-33 (IL-1F11), bind to their specific cell surface receptors, including IL-1RI, IL-1Rrp2, and T1/ST2, but use IL-1RAcP as a common co-receptor. All of these cytokines stimulate common intracellular signalling events. IL-1RAcP is ubiquitously expressed, whereas the other IL-1 receptors are more selectively expressed in different cell types. Two receptor antagonists, IL-1Ra and IL-1F5, inhibit the biologic activities of the ligands IL-1 and IL-1F6, IL-1F8, and IL-1F9, respectively. In addition, soluble IL-1RAcP inhibits the effect of IL-1 and IL-33 when present in combination with their specific soluble receptors, including IL-1RII and sST2. ERK 1/2, extracellular-regulated kinase 1/2; IL, interleukin; IRAK, interleukin-1 receptor-associated kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation 88; NF-κB, nuclear factor-kappa-B; TRAF6, tumour necrosis factor receptor-associated factor 6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2714102&req=5

Figure 1: IL-1RAcP is the common co-receptor. Several members of the IL-1 family of cytokines, including IL-1 (IL-1F1 and IL-1F2), IL-1F6, IL-1F8, IL-1F9, and IL-33 (IL-1F11), bind to their specific cell surface receptors, including IL-1RI, IL-1Rrp2, and T1/ST2, but use IL-1RAcP as a common co-receptor. All of these cytokines stimulate common intracellular signalling events. IL-1RAcP is ubiquitously expressed, whereas the other IL-1 receptors are more selectively expressed in different cell types. Two receptor antagonists, IL-1Ra and IL-1F5, inhibit the biologic activities of the ligands IL-1 and IL-1F6, IL-1F8, and IL-1F9, respectively. In addition, soluble IL-1RAcP inhibits the effect of IL-1 and IL-33 when present in combination with their specific soluble receptors, including IL-1RII and sST2. ERK 1/2, extracellular-regulated kinase 1/2; IL, interleukin; IRAK, interleukin-1 receptor-associated kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation 88; NF-κB, nuclear factor-kappa-B; TRAF6, tumour necrosis factor receptor-associated factor 6.
Mentions: IL-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 family receptor T1/ST2. IL-33 is produced as a 30-kDa propeptide [12]. The biologic effects of IL-33 are mediated upon binding to T1/ST2 and the recruitment of IL-1RAcP, the common co-receptor of IL-1α, IL-1β, IL-1F6, IL-1F8, and IL-1F9 (Figure 1). Cell signals induced by IL-33 are similar to those of IL-1 and include ERK, mitogen-activated protein kinase (MAPK) p38 and JNK, and NF-κB activation [13].

Bottom Line: A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6.In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17.Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, University Hospitals of Geneva & Department of Pathology-Immunology, University of Geneva Medical School, 1211 Geneva 14, Switzerland. cem.gabay@hcuge.ch

ABSTRACT
A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6. The introduction of these therapies should be considered a breakthrough in the management of several rheumatic diseases. However, many patients will exhibit no or only partial response to these therapies, thus emphasising the importance of exploring other therapeutic strategies. In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17. Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases. Targeting of some of these cytokines has already been tested in clinical trials with interesting results.

Show MeSH
Related in: MedlinePlus