TNF and IP-10

Overview

C-X-C motif chemokine 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the CXCL10 gene. C-X-C motif chemokine 10 is a small cytokine belonging to the CXC chemokine family. CXCL10 is secreted by several cell types in response to IFN-γ. These cell types include monocytes, endothelial cells and fibroblasts. CXCL10 has been attributed to several roles, such as chemoattraction for monocytes/macrophages, T cells, NK cells, and dendritic cells, promotion of T cell adhesion to endothelial cells, antitumor activity, and inhibition of bone marrow colony formation and angiogenesis.This chemokine elicits its effects by binding to the cell surface chemokine receptor CXCR3. (1,2,3)

Interactions

Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). One retrospective study included 38 patients admitted to the hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Serum samples were stored at −80°C. The levels of serum cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-α, IFN-γ, and interferon γ-inducible 10-kd (IP-10), were measured using a multiplex assay with the Milliplex MAP Human Cytokine/Chemokine Panel (EMD Millipore Corp., MA, USA), Bio-Plex 200 system, and Bio-Plex Manager software version 6.0 (Bio-Rad Laboratories, Inc., CA, USA). Serum IL-18 was measured using an enzyme-linked immunosorbent assay (R & D Systems, Minneapolis, MN). Ferritin was measured using a chemiluminescent immunoassay. We evaluated the association between the disease activity (global VAS and pulmonary VAS) and the levels of each cytokine. The global VAS was significantly correlated with the levels of IL-6 (r_s = 0.47), IL-8 (r_s = 0.51), IL-10 (r_s = 0.50), IL-18 (r_s = 0.53), TNF-α (r_s = 0.39), and IP-10 (r_s = 0.44).The present study revealed that IL-8, IL-10, IL-18, TNF-α, and IP-10 are significantly correlated with pulmonary disease activity and global disease activity. (4), so this recently discovered ip-10 is directly related to the disease.

Activated Cells recruitment

Because IFN-γ-inducible chemokines, Mig (CXCL9), IP-10 (CXCL10), I-TAC (CXCL11) and their receptor, CXCR3, are critical molecules in T cell trafficking and generation of effector T cells, in a Sutudy were examined the expression in the muscle biopsies of patients with sporadic inclusion body myositis (s-IBM) and disease controls. The functional role of these molecules was also studied by examining the effect and time kinetics of IFN-γ in inducing Mig and IP-10 expression in human myotubes in vitro. They found significantly high levels of Mig and IP-10 mRNA expression in s-IBM muscles compared to controls. IFN-γ upregulated the mRNA expression of Mig and IP-10 by human myotubes in a dose-dependent manner. By double-label immunohistochemistry, Mig was expressed on a subset of CD8⁺ cells and the areas of the muscle fiber in contact or contiguous to the T cells; CXCR3 was expressed only on a subset of the autoinvasive CD8⁺ T cells but not the myofibers. IP-10 and I-TAC were not detected by immunocytochemistry. The findings indicate that in s-IBM, IFN-γ is involved in the upregulation and in situ production of proinflammatory chemokines, which, in turn, participate in the recruitment of activated T cells and contribute to the self-sustaining nature of endomysial inflammation. (5)

Relevance

We confirmed autoantibodies against types I and II IFNs, GM-CSF, TNFa, TNFb, IL-1α, IL-6, IL-10, IL-12 as previously described. However, antibodies to M-CSF, IL-7, IL-17 and IL-22 have not been previously identified in autoimmune conditions. Anti-type III IFNs (IL-29, IL-28A, IL-28B), anti-IL-4 and anti-IP-10 autoantibodies are newly recognised. These data confirm that anticytokine autoantibodies are a significant presence in autoimmune diseases and extend to more cytokines than previously appreciated. The clinical and pathophysiologic roles of these autoantibodies may teach us more about etiology and pathogenesis of autoimmune diseases and we can use them as markers but larger trials are needed, but the next trials should be targeted to this newly recognized autoantibodies and maybe we could track the treatment and the disease stage evolution. (5)

 

Footnotes

1. Luster AD, Unkeless JC, Ravetch JV (1985). "Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins". Nature 315 (6021): 672–6. doi:10.1038/315672a0. PMID 3925348.

2. Luster AD, Jhanwar SC, Chaganti RS, Kersey JH, Ravetch JV (May 1987). "Interferon-inducible gene maps to a chromosomal band associated with a (4;11) translocation in acute leukemia cells". Proc. Natl. Acad. Sci. U.S.A. 84 (9): 2868–71. doi:10.1073/pnas.84.9.2868. PMC 304761. PMID 2437586.

3. O'Donovan N."Physical mapping of the CXC chemokine locus on human chromosome 4". Cytogenet. Cell Genet. 84 (1–2): 39–42. doi:10.1159/000015209. PMID 10343098.

4. Hidenaga K.IL-6, IL-8, and IL-10 Are Associated with Hyperferritinemia in Rapidly Progressive Interstitial Lung Disease with Polymyositis/Dermatomyositis. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988788/

5. Raghavanpillai R.Expression of IFN-γ-inducible chemokines in inclusion body myositis.Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10 Room 4N248, 10 Center Drive, Bethesda, MD 20892-1382, USA. http://www.jni-journal.com/article/S0165-5728%2803%2900218-2/abstract