Accepted Manuscript Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition E. Purssell PII: DOI: Reference:
S0306-9877(14)00250-3 http://dx.doi.org/10.1016/j.mehy.2014.06.015 YMEHY 7638
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
13 February 2014 17 June 2014
Please cite this article as: E. Purssell, Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy. 2014.06.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pathways and BLIMP-1 inhibition
E Purssell PhD King’s College London James Clerk Maxwell Building 57 Waterloo Road London SE1 8WA Telephone 020 7848 3021 Fax 020 7848 3555 Email [email protected]
No support in the form of grants received
1
Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pathways and BLIMP-1 inhibition Abstract Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in-vivo data on the cause of this inhibition are scarce, in-vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/ extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasmacell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs.
Background to the hypothesis Fever is one of the most common symptoms of illness in childhood. Despite its ubiquity, and lack of evidence that it has any harmful effect it is known to cause high levels of anxiety in parents and professionals alike. The proximate cause of fever is the action of prostaglandin E2 (PGE2) on cells of the anterior hypothalamus which results in heat storage or thermogenesis if this is not sufficient to raise temperature. Many of the substances that initiate this response are endogenous substances such as cytokines, most notably IL-1, IL-6 2
and TNF-α which are important components of the immune response. Because of this, the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
evolutionary conserved nature of fever, and the lack of any demonstrable harm from fever its treatment, although popular is controversial. However, demonstrating any direct benefit from fever is difficult in vivo because it is impossible to separate fever from the other behavioural, immunologic and physiological changes that occur alongside it. Furthermore, because fever is the downstream consequence of a number of different cellular events and processes it would be necessary to isolate each of these steps to establish from where any benefit arose. Nonetheless it does appear that febrile temperatures have some effect including increased tissue penetration of immunological cells; promotion of mast cell induction, attraction and degranulation; inhibition of natural killer and granulocytes; alterations in B and dendritic cell activation and maturation; and a general change from a Th1 to a Th2 response.(1) Recently concern about the routine use of antipyretic drugs in children (henceforth referred to generically as antipyretics where individual drugs are not identified) was heightened by a study suggesting that children receiving their primary and booster infant vaccines who were also given prophylactic paracetamol had lower antibody responses to some vaccine antigens compared to those not given it. The reasons for this apparent effect was not clear, the authors hypothesising that the anti-inflammatory effects of paracetamol could have interfered with the early stages of the interaction between dendritic, T and B cells.(2) Because of these and other data, current guidelines in the UK and other countries advise against the routine use of antipyretic drugs in both febrile children(3) and as prophylaxis for vaccine-related fever;(4) although the latter do still recommend that parents are given advice about their use and the appropriate dosage to treat fevers over 37.5˚C. A recent review did not show that the use of antipyretic drugs extended the length of febrile illness;(5) however, although this is an 3
outcome of importance for parents, it may not be a sensitive indicator of recovery from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
infection.
The hypothesis The hypothesis proposed here is that in addition to any non-specific effects of the use of common antipyretic drugs upon the behavioural and immunological responses to infection, many also have specific inhibitory effects upon antibody production. This is mediated primarily through interference with the mitogen activated protein kinase (MAPK) and extracellular regulated protein kinase (ERK) pathways which are important in the early stages of plasma cell differentiation, although other mechanisms of inhibition may exist. Such an effect is consistent with both in-vivo and in-vitro data showing that these drugs exert this effect most profoundly in the early stages of the specific immune response, of which plasma cell differentiation is an important part.
Hypothesis evaluation Studies were sought that examined the effect of antipyretic drugs upon antibody production, either in children in vivo on in vitro, these studies are shown in Figure 1. Four studies used paracetamol,(2, 6-8), two indomethacin(7, 9) and and one used naproxen and ibuprofen.(7) Other drugs used were either experimental COX-inhibitors or drugs not used in children; furthermore, the experimental conditions to which they were exposed did not reflect the use of these drugs in humans. There was some variation in the experimental model used, although most used human B-cells in the experimental protocol. All but two of the studies
4
were in vitro; the two clinical studies looking at the response to routine vaccination in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
children between those receiving paracetamol in the first 24 hours and those not.(2, 6)
The action of antipyretic drugs All of the drugs in common use as antipyretics work by inhibiting the action of cyclooxygenase enzymes (COX) which mediate a key step in the febrile response, namely the production of PGE2. There are two known isoforms of COX in humans, COX-1 and COX-2. The former is constitutive and is important in a number of housekeeping activities; the latter, which is inducible is thought to be most important in the febrile and inflammatory responses. Ibuprofen is a non-selective COX inhibitor, meaning that it inhibits both isoforms. The mode of action of paractamol has been the subject of some controversy, but it now appears that although it is non-selective, in most clinical situations is primarily a COX-2 inhibitor.(10) It is the non-selective action of NSAIDs that is responsible for many of their side-effects, as they interfere with housekeeping roles of COX-1 such as the maintenance of the gastric mucosa and the production of thromboxane.
Effects of cyclooxygenase inhibitors upon antibody production Because the primary action of antipyretic drugs is the inhibition of COX; one hypothesis as to their negative effect is that it is this property that is responsible for its effect on antibody production,(7) this being consistent with the finding that B cells produce inducible COX and PGE2 in response to activation. In an in vivo study where human B cells and whole blood were cultured and stimulated with anti CD40L and anti-IgM, and then exposed to 5
indomethacin and a highly selective COX-2 inhibitor SC-58125, it was found that while prior 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
to stimulation
S0306-9877(14)00250-3 http://dx.doi.org/10.1016/j.mehy.2014.06.015 YMEHY 7638
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
13 February 2014 17 June 2014
Please cite this article as: E. Purssell, Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition, Medical Hypotheses (2014), doi: http://dx.doi.org/10.1016/j.mehy. 2014.06.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pathways and BLIMP-1 inhibition
E Purssell PhD King’s College London James Clerk Maxwell Building 57 Waterloo Road London SE1 8WA Telephone 020 7848 3021 Fax 020 7848 3555 Email [email protected]
No support in the form of grants received
1
Cyclooygenase inhibitors inhibit antibody response through interference with MAPK/ERK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pathways and BLIMP-1 inhibition Abstract Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in-vivo data on the cause of this inhibition are scarce, in-vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/ extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasmacell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs.
Background to the hypothesis Fever is one of the most common symptoms of illness in childhood. Despite its ubiquity, and lack of evidence that it has any harmful effect it is known to cause high levels of anxiety in parents and professionals alike. The proximate cause of fever is the action of prostaglandin E2 (PGE2) on cells of the anterior hypothalamus which results in heat storage or thermogenesis if this is not sufficient to raise temperature. Many of the substances that initiate this response are endogenous substances such as cytokines, most notably IL-1, IL-6 2
and TNF-α which are important components of the immune response. Because of this, the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
evolutionary conserved nature of fever, and the lack of any demonstrable harm from fever its treatment, although popular is controversial. However, demonstrating any direct benefit from fever is difficult in vivo because it is impossible to separate fever from the other behavioural, immunologic and physiological changes that occur alongside it. Furthermore, because fever is the downstream consequence of a number of different cellular events and processes it would be necessary to isolate each of these steps to establish from where any benefit arose. Nonetheless it does appear that febrile temperatures have some effect including increased tissue penetration of immunological cells; promotion of mast cell induction, attraction and degranulation; inhibition of natural killer and granulocytes; alterations in B and dendritic cell activation and maturation; and a general change from a Th1 to a Th2 response.(1) Recently concern about the routine use of antipyretic drugs in children (henceforth referred to generically as antipyretics where individual drugs are not identified) was heightened by a study suggesting that children receiving their primary and booster infant vaccines who were also given prophylactic paracetamol had lower antibody responses to some vaccine antigens compared to those not given it. The reasons for this apparent effect was not clear, the authors hypothesising that the anti-inflammatory effects of paracetamol could have interfered with the early stages of the interaction between dendritic, T and B cells.(2) Because of these and other data, current guidelines in the UK and other countries advise against the routine use of antipyretic drugs in both febrile children(3) and as prophylaxis for vaccine-related fever;(4) although the latter do still recommend that parents are given advice about their use and the appropriate dosage to treat fevers over 37.5˚C. A recent review did not show that the use of antipyretic drugs extended the length of febrile illness;(5) however, although this is an 3
outcome of importance for parents, it may not be a sensitive indicator of recovery from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
infection.
The hypothesis The hypothesis proposed here is that in addition to any non-specific effects of the use of common antipyretic drugs upon the behavioural and immunological responses to infection, many also have specific inhibitory effects upon antibody production. This is mediated primarily through interference with the mitogen activated protein kinase (MAPK) and extracellular regulated protein kinase (ERK) pathways which are important in the early stages of plasma cell differentiation, although other mechanisms of inhibition may exist. Such an effect is consistent with both in-vivo and in-vitro data showing that these drugs exert this effect most profoundly in the early stages of the specific immune response, of which plasma cell differentiation is an important part.
Hypothesis evaluation Studies were sought that examined the effect of antipyretic drugs upon antibody production, either in children in vivo on in vitro, these studies are shown in Figure 1. Four studies used paracetamol,(2, 6-8), two indomethacin(7, 9) and and one used naproxen and ibuprofen.(7) Other drugs used were either experimental COX-inhibitors or drugs not used in children; furthermore, the experimental conditions to which they were exposed did not reflect the use of these drugs in humans. There was some variation in the experimental model used, although most used human B-cells in the experimental protocol. All but two of the studies
4
were in vitro; the two clinical studies looking at the response to routine vaccination in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
children between those receiving paracetamol in the first 24 hours and those not.(2, 6)
The action of antipyretic drugs All of the drugs in common use as antipyretics work by inhibiting the action of cyclooxygenase enzymes (COX) which mediate a key step in the febrile response, namely the production of PGE2. There are two known isoforms of COX in humans, COX-1 and COX-2. The former is constitutive and is important in a number of housekeeping activities; the latter, which is inducible is thought to be most important in the febrile and inflammatory responses. Ibuprofen is a non-selective COX inhibitor, meaning that it inhibits both isoforms. The mode of action of paractamol has been the subject of some controversy, but it now appears that although it is non-selective, in most clinical situations is primarily a COX-2 inhibitor.(10) It is the non-selective action of NSAIDs that is responsible for many of their side-effects, as they interfere with housekeeping roles of COX-1 such as the maintenance of the gastric mucosa and the production of thromboxane.
Effects of cyclooxygenase inhibitors upon antibody production Because the primary action of antipyretic drugs is the inhibition of COX; one hypothesis as to their negative effect is that it is this property that is responsible for its effect on antibody production,(7) this being consistent with the finding that B cells produce inducible COX and PGE2 in response to activation. In an in vivo study where human B cells and whole blood were cultured and stimulated with anti CD40L and anti-IgM, and then exposed to 5
indomethacin and a highly selective COX-2 inhibitor SC-58125, it was found that while prior 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
to stimulation
