The failure of Leishmania, an intracellular pathogen, to stimulate a proinflammatory response fol... more The failure of Leishmania, an intracellular pathogen, to stimulate a proinflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P 38 phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P 38 activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the proinflammatory response generated through TLRs.
Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- ... more Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- and anti-inflammatory cytokines in the affected tissues. The aim of this study was to investigate the association between promoter polymorphisms of TNFα and IL-10 gene with susceptibility, age of disease onset and disease severity in North Indian patients with rheumatoid arthritis (RA). SNPs at position −308 and −863 of TNF gene and −819/−592 and −1082 position of IL-10 gene were determined in 222 patients and 208 healthy controls using RFLP or ARMS method. Polymorphism TNF −308A was less prevalent among the patients (1.7%) than controls (4.9%; p = 0.01, OR: 0.32, 95% CI: 0.13–0.76). Among female patients, IL-10 −592A allele associated with higher baseline disease activity scores (5.77 ± 1.99) than −592C (5.57 ± 1.19; p = 0.04). Female patients carrying allele A of TNFα −863 had earlier age of onset of RA (33.99 ± 9.6 years) than those with allele C (36.15 ± 11.21 years; p = 0.043). In conclusion, allele A at TNFα −308 locus provides protection against RA in North Indian population while another TNF allele A at −863 position had weak association with earlier onset of disease in female patients. On the other hand promoter polymorphisms of IL-10 did not affect susceptibility but polymorphism at −819/−592A was associated with higher disease activity scores at baseline.
Rheumatic diseases form an important group of diseases in children, since early and correct diagn... more Rheumatic diseases form an important group of diseases in children, since early and correct diagnosis and management are important for their growth and development. Diagnosis of these conditions is highly supported buy laboratory investigations. This article provides an overview of the laboratory investigations that are useful in the management of rheumatic diseases in general with special emphasis on their interpretation in children.
expression is negatively regulated by the phosphatidylinositol 3-kinase (PI3K) and extracellular ... more expression is negatively regulated by the phosphatidylinositol 3-kinase (PI3K) and extracellular signal regulated kinase (ERK) 1/2 pathways in human monocyte derived macrophages (MDMs). To extend these studies, we examined the pathways downstream from PI3K in L. donovani-induced reciprocal regulation of IL-12/IL-10 axis in THP-1-derived macrophages. We show for the Wrst time that in THP-1derived macrophages and human monocytes, mTOR inhibition by rapamycin reversed L. donovani-induced IL-12 and IL-10 modulation. L. donovani-induced phosphorylation of P70S6K, a correlate of mTOR activity, in TLR-stimulated THP-1 derived macrophages. This increase in P70S6K phosphorylation was completely blocked by rapamycin (mTOR inhibitor) and partially by wortmannin (PI3K inhibitor). These observations suggest that a PI3K independent pathway is operative in the modulation of IL-12 and IL-10. Blocking of TLR2 signiWcantly attenuated IL-10 induced by the parasite, but did not aVect IL-12 production. Thus, our data suggests that intracellular network of PI3K and mTOR pathway control IL-12/IL-10 modulation by L. donovani. mTOR inhibitors may be attractive molecules to reverse this modulation and may result in control of disease.
Medical education in India is at an important crossroad; we can either continue along the same ro... more Medical education in India is at an important crossroad; we can either continue along the same road which has not led us to a desirable place or we can turn along a path to a more contemporary, and relevant location. This article is a reflection on the background, the current issues and possible future course as I see it.
The failure of Leishmania, an intracellular pathogen, to stimulate a proinflammatory response fol... more The failure of Leishmania, an intracellular pathogen, to stimulate a proinflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P 38 phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P 38 activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the proinflammatory response generated through TLRs.
Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- ... more Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- and anti-inflammatory cytokines in the affected tissues. The aim of this study was to investigate the association between promoter polymorphisms of TNFα and IL-10 gene with susceptibility, age of disease onset and disease severity in North Indian patients with rheumatoid arthritis (RA). SNPs at position −308 and −863 of TNF gene and −819/−592 and −1082 position of IL-10 gene were determined in 222 patients and 208 healthy controls using RFLP or ARMS method. Polymorphism TNF −308A was less prevalent among the patients (1.7%) than controls (4.9%; p = 0.01, OR: 0.32, 95% CI: 0.13–0.76). Among female patients, IL-10 −592A allele associated with higher baseline disease activity scores (5.77 ± 1.99) than −592C (5.57 ± 1.19; p = 0.04). Female patients carrying allele A of TNFα −863 had earlier age of onset of RA (33.99 ± 9.6 years) than those with allele C (36.15 ± 11.21 years; p = 0.043). In conclusion, allele A at TNFα −308 locus provides protection against RA in North Indian population while another TNF allele A at −863 position had weak association with earlier onset of disease in female patients. On the other hand promoter polymorphisms of IL-10 did not affect susceptibility but polymorphism at −819/−592A was associated with higher disease activity scores at baseline.
Rheumatic diseases form an important group of diseases in children, since early and correct diagn... more Rheumatic diseases form an important group of diseases in children, since early and correct diagnosis and management are important for their growth and development. Diagnosis of these conditions is highly supported buy laboratory investigations. This article provides an overview of the laboratory investigations that are useful in the management of rheumatic diseases in general with special emphasis on their interpretation in children.
expression is negatively regulated by the phosphatidylinositol 3-kinase (PI3K) and extracellular ... more expression is negatively regulated by the phosphatidylinositol 3-kinase (PI3K) and extracellular signal regulated kinase (ERK) 1/2 pathways in human monocyte derived macrophages (MDMs). To extend these studies, we examined the pathways downstream from PI3K in L. donovani-induced reciprocal regulation of IL-12/IL-10 axis in THP-1-derived macrophages. We show for the Wrst time that in THP-1derived macrophages and human monocytes, mTOR inhibition by rapamycin reversed L. donovani-induced IL-12 and IL-10 modulation. L. donovani-induced phosphorylation of P70S6K, a correlate of mTOR activity, in TLR-stimulated THP-1 derived macrophages. This increase in P70S6K phosphorylation was completely blocked by rapamycin (mTOR inhibitor) and partially by wortmannin (PI3K inhibitor). These observations suggest that a PI3K independent pathway is operative in the modulation of IL-12 and IL-10. Blocking of TLR2 signiWcantly attenuated IL-10 induced by the parasite, but did not aVect IL-12 production. Thus, our data suggests that intracellular network of PI3K and mTOR pathway control IL-12/IL-10 modulation by L. donovani. mTOR inhibitors may be attractive molecules to reverse this modulation and may result in control of disease.
Medical education in India is at an important crossroad; we can either continue along the same ro... more Medical education in India is at an important crossroad; we can either continue along the same road which has not led us to a desirable place or we can turn along a path to a more contemporary, and relevant location. This article is a reflection on the background, the current issues and possible future course as I see it.
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Papers by Dr.Sita Naik