Cardiac myofibroblasts (CMF) play a key role in infarct repair and scar formation following myocardial infarction (MI) and are also an important source of proinflammatory cytokines. We postulated that interleukin-1 alpha (IL-1alpha), a potential early trigger of acute inflammation post-MI, could stimulate human CMF to express additional proinflammatory cytokines.
Further, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients.
Interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and ELISA. IL-1alpha (0.001-10 ng/ml, 0-6 h) stimulated IL-1beta, TNFalpha and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion.
The response to IL-1alpha was much greater than with TNFalpha. Neither IL-1alpha nor TNFalpha treatment modulated CT-1 mRNA expression. Immunoblotting with phospho-specific antibodies revealed that IL-1alpha stimulated the ERK-1/2, p38 MAPK, JNK, PI3K/Akt and NF-kappaB signaling pathways.
Pharmacological inhibitor studies indicated roles for PI3K/Akt and NF-kappaB pathways in mediating IL-1beta expression, and for NF-kappaB and p38 MAPK pathways in mediating TNFalpha expression. IL-1alpha-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1alpha-induced IL-6 mRNA levels (not IL-1beta or TNFalpha), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1alpha stimulates human CMF to express IL-1beta, TNFalpha and IL-6 via specific signaling pathways; responses that are unaffected by IL-10 exposure.
Key words: cardiac fibroblasts, inflammation, signal transduction, cytokines.
Interleukin-1{alpha} Stimulates Pro-inflammatory Cytokine Expression in Human Cardiac Myofibroblasts.
Am J Physiol Heart Circ Physiol. 2009 Jul 31; Turner NA, Das A, Warburton P, O'Regan DJ, Ball SG, Porter KE
Further, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients.
Interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and ELISA. IL-1alpha (0.001-10 ng/ml, 0-6 h) stimulated IL-1beta, TNFalpha and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion.
The response to IL-1alpha was much greater than with TNFalpha. Neither IL-1alpha nor TNFalpha treatment modulated CT-1 mRNA expression. Immunoblotting with phospho-specific antibodies revealed that IL-1alpha stimulated the ERK-1/2, p38 MAPK, JNK, PI3K/Akt and NF-kappaB signaling pathways.
Pharmacological inhibitor studies indicated roles for PI3K/Akt and NF-kappaB pathways in mediating IL-1beta expression, and for NF-kappaB and p38 MAPK pathways in mediating TNFalpha expression. IL-1alpha-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1alpha-induced IL-6 mRNA levels (not IL-1beta or TNFalpha), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1alpha stimulates human CMF to express IL-1beta, TNFalpha and IL-6 via specific signaling pathways; responses that are unaffected by IL-10 exposure.
Key words: cardiac fibroblasts, inflammation, signal transduction, cytokines.
Interleukin-1{alpha} Stimulates Pro-inflammatory Cytokine Expression in Human Cardiac Myofibroblasts.
Am J Physiol Heart Circ Physiol. 2009 Jul 31; Turner NA, Das A, Warburton P, O'Regan DJ, Ball SG, Porter KE
